Intragastric device

ABSTRACT

An implant configured for ingestion by a patient. After the implant has been swallowed by the patient and is disposed within the target location, e.g. the patient&#39;s stomach, an inflation subcomponent causes the implant to expand from a compact delivery state to an expanded, volume-occupying, deployed state. In the deployed state the implant creates a sensation of satiety in the patient stomach and thereby aids in limiting food intake and obesity. After a predetermined time a deflation subcomponent is actuated and the implant reduces in size so as to allow it to pass through the remainder of the patient&#39;s digestive track. The device may further incorporate tracking and visualization subcomponents, as well as pharmaceutical delivery subcomponents.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. This application is a continuation of U.S. application Ser.No. 15/369,599, filed Dec. 5, 2016, which is a continuation of U.S.application Ser. No. 14/469,442, filed Aug. 26, 2014, now U.S. Pat. No.9,539,132, which is a continuation of U.S. application Ser. No.13/453,790 filed Apr. 23, 2012, now U.S. Pat. No. 8,845,674, which is acontinuation of U.S. application Ser. No. 12/580,132, filed Oct. 15,2009, now U.S. Pat. No. 8,162,969, which claims priority under 35 U.S.C.§ 119(e) to U.S. Provisional Application No. 61/105,932, filed Oct. 16,2008. Each of the aforementioned applications is incorporated byreference herein in its entirety, and each is hereby expressly made apart of this specification.

FIELD OF THE INVENTION

The preferred embodiments relate to devices and methods for treatingobesity. More particularly, the present invention is related tointragastric devices and methods of fabricating, deploying, monitoring,and retrieving thereof.

BACKGROUND OF THE INVENTION

Obesity is a major health problem in developed countries. Obesity putsyou at greater risk of developing high blood pressure, diabetes and manyother serious health problems. In the United States, the complicationsof overweight and obesity are estimated to affect nearly one in threeAmerican adults, with an annual medical cost of over $80 billion and,including indirect costs such as lost wages, a total annual economiccost of over $120 billion. Except for rare pathological conditions,weight gain is directly correlated to overeating.

Noninvasive methods for reducing weight include increasing metabolicactivity to burn calories and/or reducing caloric intake, either bymodifying behavior or with pharmacological intervention to reduce thedesire to eat. Other methods include surgery to reduce the stomach'svolume, banding to limit the size of the stoma, and intragastric devicesthat reduce the desire to eat by occupying space in the stomach.

Intragastric volume-occupying devices provide the patient a feeling ofsatiety after having eaten only small amounts of food. Thus, the caloricintake is diminished while the subject is satisfied with a feeling offullness. Currently available volume-occupying devices have manyshortcomings. For example, complex gastric procedures are required toinsert some devices.

U.S. Pat. No. 4,133,315, the contents of which are incorporated hereinby reference, discloses an apparatus for reducing obesity comprising aninflatable, elastomeric bag and tube combination. The bag can beinserted into the patient's stomach by swallowing. The end of theattached tube distal to the bag remains in the patient's mouth. A secondtube is snaked through the nasal cavity and into the patient's mouth.The tube ends located in the patient's mouth are connected to form acontinuous tube for fluid communication through the patient's nose tothe bag. Alternatively, the bag can be implanted by a gastric procedure.The bag is inflated through the tube to a desired degree before thepatient eats so that the desire for food is reduced. After the patienthas eaten, the bag is deflated. The tube extends out of the patient'snose or abdominal cavity throughout the course of treatment.

U.S. Pat. Nos. 5,259,399, 5,234,454 and 6,454,785, the contents of whichare incorporated herein by reference, disclose intragastricvolume-occupying devices for weight control that must be implantedsurgically.

U.S. Pat. Nos. 4,416,267; 4,485,805; 4,607,618; 4,694,827; 4,723,547;4,739,758; 4,899,747 and European Patent No. 246,999, the contents ofwhich are incorporated herein by reference, relate to intragastric,volume-occupying devices for weight control that can be insertedendoscopically. Of these, U.S. Pat. Nos. 4,416,267; 4,694,827; 4,739,758and 4,899,747 relate to balloons whose surface is contoured in a certainway to achieve a desired end. In U.S. Pat. Nos. 4,416,267 and 4,694,827,the balloon is torus-shaped with a flared central opening to facilitatepassage of solids and liquids through the stomach cavity. The balloon ofU.S. Pat. No. 4,694,827 has a plurality of smooth-surfaced convexprotrusions. The protrusions reduce the amount of surface area whichcontacts the stomach wall, thereby reducing the deleterious effectsresulting from excessive contact with the gastric mucosa. Theprotrusions also define channels between the balloon and stomach wallthrough which solids and liquids may pass. The balloon of U.S. Pat. No.4,739,758 has blisters on its periphery that prevent it from seatingtightly against the cardia or pylorus.

The balloons of U.S. Pat. Nos. 4,899,747 and 4,694,827, are inserted bypushing the deflated balloon and releasably attached tubing down agastric tube. U.S. Pat. No. 4,723,547 discloses a specially adaptedinsertion catheter for positioning its balloon. In U.S. Pat. No.4,739,758, the filler tube effects insertion of the balloon. In U.S.Pat. No. 4,485,805, the balloon is inserted into a finger cot that isattached by string to the end of a conventional gastric tube that isinserted down the patient's throat. The balloon of European Patent No.246,999 is inserted using a gastroscope with integral forceps.

In U.S. Pat. Nos. 4,416,267; 4,485,805; 4,694,827; 4,739,758; 4,899,747and European Patent No. 246,999, the balloon is inflated with a fluidfrom a tube extending down from the patient's mouth. In these patents,the balloon also is provided with a self-sealing hole (U.S. Pat. No.4,694,827), injection site (U.S. Pat. Nos. 4,416,267, 4,899,747),self-sealing fill valve (U.S. Pat. No. 4,485,805), self-closing valve(European Patent No. 246,999) or duck-billed valve (U.S. Pat. No.4,739,758). U.S. Pat. No. 4,723,547 uses an elongated thick plug and theballoon is filled by inserting a needle attached to an air sourcethrough the plug.

U.S. Pat. No. 4,607,618 describes a collapsible appliance formed ofsemi-rigid skeleton members joined to form a collapsible hollowstructure. The appliance is not inflatable. It is endoscopicallyinserted into the stomach using an especially adapted bougie having anejector rod to release the collapsed appliance. Once released, theappliance returns to its greater relaxed size and shape.

U.S. Pat. No. 5,129,915, the contents of which are incorporated hereinby reference, relates to an intragastric balloon that is intended to beswallowed and that inflates automatically under the effect oftemperature. U.S. Pat. No. 5,129,915, discusses three ways that anintragastric balloon might be inflated by a change in temperature. Acomposition comprising a solid acid and non-toxic carbonate orbicarbonate is separated from water by a coating of chocolate, cocoapaste or cocoa butter that melts at body temperature. Alternatively,citric acid and an alkaline bicarbonate coated with non-toxic vegetableor animal fat melting at body temperature and which placed in thepresence of water, would produce the same result. Lastly, the solid acidand non-toxic carbonate or bicarbonate are isolated from water by anisolation pouch of low-strength synthetic material which it will sufficeto break immediately before swallowing the bladder. Breaking theisolation pouches causes the acid, carbonate or bicarbonate and water tomix and the balloon to begin to expand immediately. A drawback ofthermal triggering of inflation as suggested by U.S. Pat. No. 5,129,915is that it does not afford the degree of control and reproducibility ofthe timing of inflation that is desirable and necessary in a safeself-inflating intragastric balloon.

SUMMARY OF THE INVENTION

A free-floating, intragastric, volume-occupying device that can beinserted into the stomach simply by the patient swallowing it andletting peristalsis deliver it into the stomach in the same manner thatfood is delivered is desirable.

Volume-occupying devices and methods for manufacturing, deploying,inflating, tracking, deflating and retrieving of such devices areprovided. The devices and methods of the preferred embodiments may beemployed for treating obesity. Methods employing the device of thepreferred embodiments need not utilize invasive procedures, but ratherthe device may simply be swallowed by a patient. Once in the stomach ofthe patient, the device will increase in volume. After a predeterminedtime period has passed, or upon demand, the device will decrease involume and pass through the remainder of the patient's digestive tract.

In certain preferred embodiments the inflation subcomponent of thedevice is incorporated within the interior or into the wall of thevolume-occupying subcomponent. Inflation may be achieved through achemical reaction between reactive agents producing a gas or other fluidbyproduct. Various types of environmentally sensitive and mechanicalbarriers may be employed to compartmentalize the reactive agents so asto delay inflation until the device is in the patient's stomach.Alternatively, inflation of the volume-occupying subcomponent may beachieved by electrical or mechanical means actuated by an exteriorsignal such as radiofrequency (RF) or a magnetic field or pulse.Alternatively, the volume-occupying subcomponent may be comprised of athermo-elastic polymer susceptible to volume expansion upon introductionto a predefined temperature or to the pH environment of the stomach.Alternatively, the volume-occupying subcomponent may be comprised of amemory polymer designed to form an expanded volume-occupyingsubcomponent in its relaxed state and that is restricted to aswallowable size prior to ingestion with such restriction breaking ordegrading in the stomach to allow the volume-occupying subcomponent toexpand. Inflation may also be achieved by use of a removable tube thatinitially remains in fluid contact with the device after it has beenswallowed by the patient.

In other embodiments, the volume-occupying subcomponent of devices maybe formed by injection, blow or rotational molding of a flexible,gas-impermeable, biocompatible material, such as, for example,polyurethane or polyethylene terephthalate. Materials that may be usedto improve the gas impermeability of the volume-occupying subcomponentinclude, but are not limited to, silicon oxide (SiOx), gold or any noblemetal, PET coated with saran, conformal coatings and the like. Tofacilitate greater gas-impermeable characteristics, the volume-occupyingsubcomponent may be further coated with one or more gas-barriercompounds. Alternatively, the volume-occupying subcomponent may beformed of a Mylar polyester film coating or kelvalite, silver oraluminum as a metallicized surface to provide a gas impermeable barrier.The volume-occupying subcomponent may further incorporate a weightingelement either located within its interior or within its wall.

In certain preferred embodiments, deflation subcomponents may beintegrated into the wall of the volume-occupying subcomponent or at thehead region of the volume-occupying subcomponent at the end of thevolume-occupying subcomponent shaft. Deflation of the device may beeither time dependant or on-demand. Deflation may be triggered by, forexample, chemical degradation, lithotripsy techniques, externallyapplied magnetic field, remotely activated microchips; voltagedifferences; and light degrading compounds.

In further embodiments, the device employs a delivery state in which thedevice is packaged such that the device may be swallowed while producingminimal discomfort to the patient. In a delivery state, the device maybe packaged into a capsule. Alternatively, the device may be coated witha material operable to confine the device and facilitate swallowing.Various techniques may also be employed to ease swallowing of the deviceincluding, for example, wetting, temperature treating, lubricating, andtreating with pharmaceuticals such as anesthetics.

In other embodiments, the devices may incorporate a tracking orvisualization component that enables physicians to determine thelocation and/or orientation of the device within the patient's body.Tracking subcomponents may include incorporating a barium stripe orgeometric shape into the wall of the volume-occupying subcomponent.Tracking and visualization, may also be achieved by incorporation of amicrochip, infrared LED tag, ultraviolet absorbing compounds,fluorescent or colored compounds and incorporation of metalized stripsand patterns into the volume-occupying subcomponent or othersubcomponents of the device. Such techniques may also be used to obtaincertain device specific information and specifications while the deviceremains inside the patient's body.

In other preferred embodiments, the device may also serve as a means fordelivering pharmaceuticals to a patient, either in conjunction withobesity treatment or independent thereof. For example, the device may becoated or otherwise impregnated with pharmaceuticals for control ofstomach acid, treatment of gastroesophageal reflux disease (GERD),nausea, control of body weight, control of blood glucose, modulation ofgastric emptying, modulation of gastric absorption, modulation ofhormone levels and satiety signaling.

In a first aspect, a swallowable, self-inflating intragastric balloonsystem is provided comprising: a balloon comprising a self-sealing valvesystem attached to a wall of the balloon in a central lumen of theballoon by an adhesive with a shear force greater than about 40 N, theself-sealing valve system comprising a septum, a retaining structure,and a continuous ring, wherein the septum has a durometer that is lessthan a durometer of the retaining structure, wherein the continuous ringis configured to exert a compressive force on the septum, wherein theballoon has a weight of less than about 15 g, wherein the balloon isconfigured to have a shape upon full inflation selected from the groupconsisting of ellipsoid, spheroid, and oblate spheroid, and wherein theballoon is configured to have a volume of from about 90 cm³ to about 350cm³ upon full inflation; an inner container within the central lumen ofthe balloon, the inner container containing from about 0.28 grams toabout 4 grams of an inflation agent, wherein up to about 80 wt. % of atotal amount of the inflation agent is powdered citric acid, with aremainder of the inflation agent comprising powdered sodium bicarbonate;and an outer container configured to be swallowed by a patient withoutassistance, the outer container comprising a material and a structureconfigured to control timing of inflation, and containing the innercontainer and the balloon in a compacted state.

In an embodiment of the first aspect, the retaining structure comprisesa material selected from the group consisting of silicone, rubber,acrylic, epoxy, a thermoplastic elastomer, and a thermoplasticpolyurethane.

In an embodiment of the first aspect, the system further comprises aninoculation spacer situated in the central lumen of the balloon adjacentto the septum.

In an embodiment of the first aspect, the activation agent comprises anaqueous solution of up to about 50% citric acid in solution into thecentral lumen of the balloon, and wherein a total amount of citric acidin the inflation agent and the activation agent combined creates a pH ofabout 6 or less in a residual liquid remaining after completion of a CO₂generating reaction of the inflation agent.

In an embodiment of the first aspect, the inoculation spacer is in aform of a tube or a cylinder.

In an embodiment of the first aspect, the balloon is situated in theouter container in a deflated and folded state, wherein folds of theballoon are configured to localize an activation agent injected into thecentral lumen of the balloon adjacent to the inner container.

In an embodiment of the first aspect, the system further comprises avoid space in the outer container configured for occupation byactivation agent injected inside the central lumen of the balloon,wherein a volume of the void space is from about 0.3 ml to about 4.5 ml.

In an embodiment of the first aspect, the septum has a durometer ofabout 20 Shore A to about 60 Shore D, and wherein the retainingstructure has a durometer of from about 40 Shore D to about 70 Shore D,

In an embodiment of the first aspect, the continuous ring isradio-opaque.

In an embodiment of the first aspect, the balloon is configured to have,upon full inflation, an internal nominal pressure at about 37° C. offrom about 0 Pa to about 103421 Pa.

In an embodiment of the first aspect, the balloon is configured to have,upon full inflation, a nominal radius of from about 2.5 cm to about 7.6cm, a nominal height of from about 0.6 cm to about 7.6 cm.

In an embodiment of the first aspect, from about 10 wt. % to about 80wt. % of the total amount of the inflation agent is powdered citricacid.

In an embodiment of the first aspect, the inner container has a longestdimension of from about 1.9 cm to 2.7 cm, a width of from about 0.6 cmto about 1 cm, and a volume of from about 0.41 ml to about 1.37 ml.

In an embodiment of the first aspect, the outer container has a longestdimension of from about 2.4 cm to 6.3 cm, a width of from about 0.9 cmto about 2.4 cm, and a volume of from about 1.2 ml to about 8.25 ml.

In an embodiment of the first aspect, at least one of the innercontainer or the outer container comprises gelatin.

In an embodiment of the first aspect, at least one of the innercontainer or the outer container comprises a gelatin capsule.

In an embodiment of the first aspect, the balloon is fully sealed 360degrees around with no external opening or orifice to the central lumen.

In an embodiment of the first aspect, the balloon has a smooth surface.

In a second aspect, a method for fabricating a swallowable,self-inflating intragastric balloon system is provided, the methodcomprising: adhering a self-sealing valve system to a first half of awall of a balloon by an adhesive with a shear force greater than about40 N, the self-sealing valve system comprising a septum, a retainingstructure, and a continuous ring, wherein the septum has a durometerthat is less than a durometer of the retaining structure, wherein thecontinuous ring is configured to exert a compressive force on theseptum; joining the first half of the wall of the balloon to a secondhalf of the wall of the balloon, wherein either the first half of thewall of the balloon or the second half of the wall of a ballooncomprises a hole having a smallest dimension of at least about 0.6 cm,and a largest dimension of no more than about 3.8 cm; inverting theballoon through the hole; placing an inner container within a centrallumen of the inverted balloon, the inner container containing from about0.28 grams to about 4 grams of an inflation agent, wherein up to about80 wt. % of a total amount of the inflation agent is powdered citricacid, with a remainder of the inflation agent comprising powdered sodiumbicarbonate; and applying a patch of a material to seal the hole,whereby a balloon having a smooth outer surface is obtained, wherein theballoon has a weight of less than about 15 g, wherein the balloon isconfigured have a shape upon full inflation selected from the groupconsisting of ellipsoid, spheroid, and oblate spheroid, and wherein theballoon is configured to have a volume of from about 90 cm³ to about 350cm³ upon full inflation.

In an embodiment of the second aspect, joining comprises welding oradhesively adhering.

In a third aspect, a method for inflating a swallowable, self-inflatingintragastric balloon is provided, comprising: a balloon comprising aself-sealing valve system attached to a wall of the balloon in a centrallumen of the balloon by an adhesive with a shear force greater thanabout 40 N, the self-sealing valve system comprising a septum, aretaining structure, and a continuous ring, wherein the septum has adurometer that is less than a durometer of the retaining structure,wherein the continuous ring is configured to exert a compressive forceon the septum, wherein the balloon has a weight of less than about 15 g,wherein the balloon is configured have a shape upon full inflationselected from the group consisting of ellipsoid, spheroid, and oblatespheroid, and wherein the balloon is configured to have a volume of fromabout 90 cm³ to about 350 cm³ upon full inflation; an inner containerwithin the central lumen of the balloon, the inner container containingfrom about 0.28 grams to about 4 grams of an inflation agent, wherein upto about 80 wt. % of a total amount of the inflation agent is powderedcitric acid, with a remainder of the inflation agent comprising powderedsodium bicarbonate; an outer container configured to be swallowed by apatient without assistance, the outer container comprising a materialand a structure configured to control timing of inflation, andcontaining the inner container and the balloon in a compacted state; andan inoculation spacer configured to guide a needle into the septum forinjection of an activation agent into the central lumen of the balloonwhile avoiding puncture of the inner container, wherein the inoculationspacer is situated in the outer container, adjacent to the septum;injecting an activation agent into the central lumen of the balloonthrough the wall of the balloon atop the septum and through the septumitself using the inoculation spacer as a guide, whereby degradation ofthe inner container is initiated; thereafter allowing the system to beswallowed by a patient in need thereof; degrading the outer container ina stomach of the patient; initiating inflation by contact of theactivation agent with the inflation agent via degradation of the innercontainer, wherein inflation is initiated no earlier than about 30seconds after injection of the activation agent; unfolding the balloonvia inflation from about 60 seconds to about 15 minutes after injectionof activation agent; and inflating the balloon such that at least about10% of the occupyable volume of the balloon is filled within about 30minutes, at least about 60% of the occupyable volume of the balloon isfilled within about 12 hours, and at least about 90% of the occupyablevolume of the balloon is filled within about 24 hours.

In an embodiment of the third aspect, the activation agent issubstantially localized in the balloon adjacent to the inner containerupon injection.

In an embodiment of the third aspect, the balloon is compacted suchthat, upon initiating inflation, the balloon unfolds in a manner thatcreates a surface area sufficiently large so as to prohibit the balloonfrom passing through the pyloric sphincter.

In an embodiment of the third aspect, a pH of any remnant liquid insidethe central lumen of the balloon is acidic such that any balloon leakageor breach that allows stomach acid to enter the balloon does notinitiate reinflation of the balloon.

In an embodiment of the third aspect, allowing the system to beswallowed by a patient in need thereof comprises swallowing, via normalperistalsis, the outer container containing the inner container,inoculation spacer, and the balloon in a compacted state.

In an embodiment of the third aspect, the inner container comprises agelatin capsule.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of an exemplary intragastricvolume-occupying device in an inflated state, in accordance with apreferred embodiment.

FIG. 1B is a cross-sectional view of an exemplary intragastricvolume-occupying device in an inflated state, in accordance with apreferred embodiment.

FIG. 2A is a cross-sectional view of an exemplary intragastricvolume-occupying device in a delivery state, in accordance with apreferred embodiment.

FIG. 2B is a perspective view of an exemplary intragastricvolume-occupying device in a delivery state, in accordance with apreferred embodiment.

FIG. 3A is a cross-sectional view of an exemplary intragastricvolume-occupying device in a delivery state, in accordance with apreferred embodiment.

FIG. 3B is a perspective view of an exemplary intragastricvolume-occupying device in a delivery state, in accordance with apreferred embodiment.

FIG. 4A is a cross-sectional view of an exemplary intragastricvolume-occupying device in a delivery state, in accordance with apreferred embodiment.

FIG. 4B is a perspective view of an exemplary intragastricvolume-occupying device in a delivery state, in accordance with apreferred embodiment.

FIG. 5A is a cross-sectional view of an exemplary intragastricvolume-occupying device in a delivery state, in accordance with apreferred embodiment.

FIG. 5B is a perspective view of an exemplary intragastricvolume-occupying device in a delivery state, in accordance with apreferred embodiment.

FIG. 6 is a perspective view of an exemplary inflation subcomponent in adelivery state, in accordance with a preferred embodiment.

FIG. 7 is a perspective view of an exemplary inflation subcomponent in adelivery state, in accordance with a preferred embodiment.

FIG. 8 is a perspective view of an exemplary inflation subcomponent in adelivery state, in accordance with a preferred embodiment.

FIG. 9 is a perspective view of an exemplary inflation subcomponent in adelivery state, in accordance with a preferred embodiment.

FIGS. 10A and B are cross-sectional views of an exemplary inflationsubcomponent, in accordance with a preferred embodiment.

FIGS. 11A and B are perspective views of an exemplary intragastricvolume-occupying device in an inflated state, in accordance with apreferred embodiment.

FIG. 12 is a cross-sectional view of an inflation subcomponent, inaccordance with a preferred embodiment.

FIG. 13 is a cross-sectional view of an inflation subcomponent, inaccordance with a preferred embodiment.

FIG. 14 is a cross-sectional view of an inflation subcomponent, inaccordance with a preferred embodiment.

FIGS. 15A and B are cross-sectional views of an exemplary intragastricvolume-occupying device and associated inflation subcomponent, inaccordance with a preferred embodiment.

FIGS. 16A and B are perspective views of an exemplary intragastricvolume-occupying device and associated deflation subcomponent in aninflated state, in accordance with a preferred embodiment.

FIGS. 17A and B are perspective views of a deflation subcomponent, inaccordance with a preferred embodiment.

FIG. 18 is a cross-sectional view of a deflation subcomponent, inaccordance with a preferred embodiment.

FIG. 19 is a cross-sectional view of a deflation subcomponent, inaccordance with a preferred embodiment.

FIGS. 20A-D are cross-sectional views of a deflation subcomponent, inaccordance with a preferred embodiment.

FIGS. 21A and B are cross-sectional views of a deflation subcomponent,in accordance with a preferred embodiment.

FIGS. 22A-C are cross-sectional views of a delivery subcomponent, inaccordance with a preferred embodiment.

FIG. 23 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 24 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 25 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 26 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 27 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 28 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 29 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 30 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 31 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 32 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 33 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 34 is a perspective view of an exemplary volume-occupyingsubcomponent in an expanded state deployed within a patient's stomach,in accordance with a preferred embodiment.

FIG. 35 is a perspective view of an exemplary visualization and trackingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIG. 36 is a perspective view of an exemplary visualization and trackingsubcomponent in a deflated or contracted state, in accordance with apreferred embodiment.

FIG. 37 is a perspective view of an exemplary visualization and trackingsubcomponent in an expanded state, in accordance with a preferredembodiment.

FIGS. 38A and B are perspective views of exemplary drug deliverysubcomponents in expanded states, in accordance with a preferredembodiment.

FIGS. 39A and B are perspective views of exemplary drug deliverysubcomponents in expanded states, in accordance with a preferredembodiment.

FIGS. 40A and B are perspective views of exemplary drug deliverysubcomponents, in accordance with a preferred embodiment.

FIGS. 41A and B are perspective views of exemplary drug deliverysubcomponents, in accordance with a preferred embodiment.

FIG. 42 is an illustration of various views of exemplary device inaccordance with a preferred embodiment.

FIG. 43A-C is an illustration of various methods of assembling devicesin accordance with a preferred embodiment.

FIGS. 44A and B depicts components of a swallowable, self-inflatingintragastric balloon system. FIG. 44A depicts a silicone head 441 withradioopacity ring 442, trimmed 30D silicone septum 443, Nylon 6inoculation spacer 444, folded balloon 445, inner container 446, andouter container 447 as constituents of the system in unassembled form.

FIG. 44B depicts a fully assembled outer container 447 including venthole 448 aligned with septum 449 for puncture to inject liquidactivation agent.

FIGS. 45A-B depict a silicone head 451 and opacity ring 452 of aself-sealing valve system 450 of a preferred embodiment: FIG. 45A is aperspective view; and FIG. 45B is a side view.

FIGS. 46A-C depict a wedge-shaped septum 460 of a preferred embodiment:FIG. 46A is a perspective view; FIG. 46B is a side view; and FIG. 46C isa top view.

FIGS. 47A-E depict a cupped needle stop (inoculation spacer) 470 of apreferred embodiment: FIG. 47A is a perspective view; FIG. 47B is a topview; FIG. 47C is a bottom view; FIG. 47D is a side view; and FIG. 47Eis a cross section view through A-A.

FIGS. 48A-G depict a process for folding a balloon of a preferredembodiment for placement in an outer container. The balloon 480 containsan inner container 481. A self-sealing valve system 482 is adhesivelyadhered to the interior of the wall 483 of the balloon, and the invertedconfiguration of the balloon is provided by inversion through a holesealed with a patch 484.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate a preferred embodimentof the present invention in detail. Those of skill in the art willrecognize that there are numerous variations and modifications of thisinvention that are encompassed by its scope. Accordingly, thedescription of a preferred embodiment should not be deemed to limit thescope of the present invention.

The term “degradable” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a process by which structural integrity ofthe balloon is compromised (e.g., by chemical, mechanical, or othermeans (e.g., light, radiation, heat, etc.) such that deflation occurs.The degradation process can include erosion, dissolution, separation,digestion, disintegration, delamination, comminution, and other suchprocesses.

The term “swallowable” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to ingestion of a balloon by apatient such that the outer capsule and its constituents are deliveredto the stomach via normal peristalsis movement. While the systems ofpreferred embodiments are swallowable, they are also configured byingestion by methods other than swallowing. The swallowability of thesystem is derived, at least in part, by the outer container size, whichis sufficient to contain the inner container and its constituents, anamount of activation agent injected prior to administration, the balloonsize, and the balloon material thickness. The system is preferably of asize less than the average normal esophagus diameter.

Described herein is an orally ingestible device that is able to traversethe alimentary canal. The device may be useful, for example, as anintragastric volume-occupying device. The device overcomes one or moreof the above-described problems and shortcomings found in currentintragastric volume-occupying devices.

FIG. 1A is an illustration of a device 10 in an inflated state accordingto the present invention. FIG. 1B is a cross-sectional illustration ofthe device 10. Certain preferred embodiments employ a volume-occupyingsubcomponent, an inflation subcomponent, a deflation subcomponent, and adelivery subcomponent. Devices according to the present inventions mayfurther comprise a tracking subcomponent and/or a drug deliverysubcomponent. FIGS. 2A through 5B are illustrations of the devices 10according to the present invention that are in a delivery state, e.g.,the devices 10 are in a compact, non-inflated state. FIGS. 2A, 3A, 4A,and 5A are cross-sectional views of the devices 10 and FIGS. 2B, 3B, 4B,and 5B are perspective views of the corresponding devices 10. Generally,in the delivery state, the device 10 is in the form of an ingestiblecapsule or other similarly sized and shaped package.

In order to more clearly describe the subject matter of the preferredembodiments, different embodiments of the same subcomponent will bedescribed under a single relevantly-titled subheading. This organizationis not intended to limit the manner in which embodiments of differentsubcomponents may be combined in accordance with the present invention.

Inflation Subcomponents

Devices according to the present invention are intended for ingestion bya patient and deployment without the need to resort to invasive methods.It is therefore desirable that the device of the preferred embodimentsbe operable to conform to a compact delivery state which can beswallowed by a patient with minimal discomfort. Once in the stomach, itis desirable for the device to assume a substantially larger deployedstate. In order to achieve the transition from a delivery state to adeployed state the device is subjected to an inflation step performed byan inflation subcomponent.

The inflation subcomponent may generally be located entirely within thevolume-occupying subcomponent or integrated into the wall of thevolume-occupying subcomponent. As will be further described below, theinflation subcomponent may be self-contained, e.g., all elementsnecessary for inflation of the volume-occupying subcomponent aresituated on or within the device at the time the patient ingests thedevice in the delivery state. Alternatively, in order to inflate, theinflation subcomponent may require outside inputs such as fluids,activation agents, or externally generated signals or other forms ofcommunication.

In certain preferred embodiments, the volume-occupying subcomponent isfilled with a fluid using tubing which is subsequently pulled away fromthe volume-occupying subcomponent. One end of the volume-occupyingsubcomponent has a port connected to tubing of sufficient length thatwhen unwound can span the entire length of the esophagus, from mouth tostomach. This tubing is connected to the volume-occupying subcomponentwith a duct valve that can tear away from the volume-occupyingsubcomponent and self-seal once the volume-occupying subcomponent isinflated. A physician secures one end of the tubing as the patientswallows the device. Once the device is residing within the stomach, thephysician uses the tube to transmit a fluid, such as air, into thevolume-occupying subcomponent and thereby inflate it. After thevolume-occupying subcomponent is fully inflated, the tubing is releasedand can be pulled out from inside the patient.

The tube may be released in a number of manners that are either novel orknown in the art. For example, the tubing may be detached by thephysician by applying a gentle force, or tug, on the tubing.Alternatively, the tubing may be detached by the physician by actuatinga remote release, such as a magnetic or electronic release.Additionally, the tubing may be released from the volume-occupyingsubcomponent by an automatic ejection mechanism. Such an ejectionmechanism may be actuated by the internal pressure of the inflatedvolume-occupying subcomponent. For example, the ejection mechanism maybe sensitive to a specific pressure beyond which it will open so as torelease any excess pressure and simultaneously release the tube. Thisembodiment provides a desirable feature through combining release of thetubing with a safety valve that serves to avert accidental overinflation of the volume-occupying subcomponent in the patient's stomach.

This automatic release embodiment also provides the benefit that thedevice inflation step may be more closely monitored and controlled bythe physician. Current technology allows for a self-inflatingintragastric volume-occupying subcomponent which generally begins toinflate in a four minute timeframe after injection with an activationagent such as citric acid. A drawback to this approach is that thevolume-occupying subcomponent may begin to inflate prior to thephysician knowing whether the device is truly residing within thestomach. In some cases, the capsule may still be in the esophagus at thetime when inflation starts to occur. Patients with gastric dumpingsyndrome or rapid gastric emptying may end up with the volume-occupyingsubcomponent in their small intestine prior to the time that inflationoccurs. It would therefore be a safer alternative to inflate thevolume-occupying subcomponent on command, once the physician canascertain that the volume-occupying subcomponent is residing in thecorrect location.

In certain other preferred embodiments, the volume-occupyingsubcomponent is inflated by one or more chemical reactions that takeplace once the device is positioned within the stomach. Such chemicalreactions may include, but are not limited to: combining wax, O₂, andheat to form CO₂ and H₂O; combining NaHCO₃ and acetic acid or citricacid to form CO₂ and H₂O; combining sugar and yeast to form ethanol andCO₂; combining C_(x)H_(y); an xO₂, and energy to form xCO₂ and yH₂O;combining sulfur and O₂ to form SO₂; combining potassium and water toform H₂ and KOH; combining C₆H₁₂O₆ and yeast to form 2C₂H₅OH and 2CO₂;combining cupric bicarbonate and heat to form CuO, water and CO₂;combining magnesium and H₂SO₄ to form H₂ and MgSO₄; combining NaHCO₃ andHCl to form water, CO₂, and NaCl; a combustion reaction; or combiningdry ice and heat to form CO₂. In such embodiments it may or may not benecessary to compartmentalize or otherwise separate the components ofthe chemical reaction while the device is in the delivery state. Whencompartmentalization is necessary, one skilled in the art willunderstand that various methods exist for temporarily separating thecomponents, including but not limited to employing: temperaturesensitive barriers, energy sensitive barriers, time sensitive barriers,light sensitive barriers, other environmentally sensitive barriers,chemically sensitive barriers, and mechanical barriers.

For example, the embodiments illustrated in FIGS. 6 and 8 have aninflation subcomponent 100 that includes a liquid 110 and a solidreactant 120 packaged into a two-part capsule 130. For example, thesolid reactant 120 may be in the form of a carbonate such asbicarbonate. The liquid 110 and solid reactant 120 are separated by amechanical barrier 150 present within the capsule 130. To initiate thechemical reaction between the liquid 110 and the solid reactant 120, aforce is applied to the capsule 130 causing the capsule 130 to break andthe liquid 110 and solid reactant 120 to mix and react with one another.The resulting reaction produces a gas byproduct which thereby inflatesthe volume-occupying subcomponent with which the inflation subcomponent100 is associated. Other configurations are also contemplated, e.g., aninflation agent mixture (e.g., solid sodium bicarbonate and solid citricacid) in an inner container, where gas generation is initiated by anactivation agent (e.g., water, or an aqueous citric acid solution) thatcauses dissolution or degradation of the inner container so as tocontact the inflation agent mixture.

In one embodiment, the barrier or barriers may incorporate anenvironmentally-sensitive shape-memory material, e.g. a polymer or ametal such as Nitinol (a shape memory alloy of nickel and titanium). Theshape-memory material may, for example, be treated to changeconfiguration at or above a certain temperature thereby mechanicallydisrupting the barrier and allowing mixing of the inflationaryreactants. For example, such disruption may be triggered when theNitinol contained in the barrier is heated to its transition temperatureby the environment of the stomach (in which case it may be necessary tostore the device below room temperature prior to administration) or suchdisruption may be triggered when the Nitinol is heated to its transitiontemperature above the body temperature. Such source of heat may begenerated by any means of heat generation described below. Thetransition temperature of Nitinol may be modified so as to achieve themetal's configuration change at the desired temperature or temperaturerange.

It may be advantageous to delay the initiation of such reaction untilthe volume-occupying subcomponent has had sufficient time to reach thestomach. Accordingly, as illustrated in FIG. 7, another embodiment ofthe device may contain an additional soluble barrier 160 positionedbetween the solid reactant 120 and the mechanical barrier 150 to bebroken. Such additional barrier 160 may be, for example, a dissolvablepolysaccharide barrier that dissolves within several minutes of contactwith the liquid 110 such that inflation agents do not mix and thechemical reaction does not occur until several minutes following thebreaking of the capsule 130.

In another example, as illustrated in FIG. 9, the barrier 150 separatingthe chemical inflation agents is connected to the end of a string ortubing 170 whose length is approximately the distance from the patient'smouth to stomach. In this example, a distal end 172 of the string ortubing 170 is held by the administrator of the device to the patientwhile the device is being administered to the patient, and the length ofthe string or tubing 170 provides a measure indicating when the devicehas reached the stomach. Upon the device's reaching of the stomach, theadministrator of the device can then pull the distal end 172 of string170 to disrupt or move the barrier 150 sufficiently for the chemicalagents to mix and react with one another and initiate the inflationprocess. The proximal end 174 of the string or tube 170 may be directlyconnected to the barrier 150 and, upon its detachment from the barrier150, pass through a self-sealing portion of the volume-occupyingsubcomponent wall (not shown). Alternatively, the proximal end 174 ofthe string or tube 170 need not be directly connected to the barrier 150and instead can be connected to the device in any manner such thattension from a pull of the string 170 is transferred to the barrier 150sufficiently to cause its movement or breakage. For example, the stringor tubing 170 may be connected to a portion of the volume-occupyingsubcomponent wall that is connected to a portion of the barrier 150. Itmay be necessary for the outer coating of the device to dissolve atleast partially so that tension from the pull may be transferred to thebarrier 150. The pull of the string 170 will also initiate or contributeto the detachment of the string 170 from the device. The string 170 maybe able to detach from the device as a result of the pull from theadministrator or a combination of such pull and other means. Forexample, the proximate end 174 of string 170 or the materials attachingit to the device may be comprised of materials that dissolve or degradein the stomach environment that facilitate the detachment of the string170.

In another example, the barrier separating the chemical inflation agentsis ultraviolet, or UV, sensitive. The device in the delivery state mayinclude a UV blocking outer layer that can be removed immediately priorto ingestion of the device. Once the UV blocking layer is removed the UVsensitive barrier is exposed to UV. The exposure initiates a timeddegradation of the barrier, subsequent mixing of the agents, andinflation of the volume-occupying subcomponent. Such UV exposure to thebarrier may occur prior to administration of the device to the patientor may be performed following administration of the device to thepatient. UV exposure to the barrier following administration of thedevice to the patient may be accomplished by exposing the barrier to aUV light source external to the volume-occupying subcomponent, e.g., byinserting an endoscope or wand with a UV light source at its end orallydown the gastrointestinal tract and which then emits UV light at thebarrier. In such case the device may be tethered to the UV light sourcesuch that the UV light source and the device are administered orallyconcurrently or one immediately following the other, resulting in the UVlight source and the device being located proximate to each other toallow for accurate direction of UV light onto the barrier.Alternatively, UV exposure to the barrier following administration ofthe device to the patient may be accomplished by exposing the barrier toa UV source within the volume-occupying subcomponent that is activatedat the time of administration to the patient to emit UV light.

In another embodiment, an intragastric volume-occupying device isengineered with a power source and radiofrequency transformer such thatan external wireless RF signal is able to be transformed into electricenergy and create a voltage difference to inflate the volume-occupyingsubcomponent. The RF signal may be received by means of an antennaadjacent to the power source. For example, the external RF energy may beutilized to power a pump to pump stomach acids into an internalreservoir of the device to react with an inflationary agent such as acarbonate. Alternatively, the external RF energy may be used to open avalve or barrier situated between inflation reactants.

In an alternative example, inflation may be achieved by means of apolymer microfilm situated adjacent to at least one inflationaryreactant. The electric energy triggered by the RF signal causes themicrofilm to heat at least one reactant which in turn may be sufficientto generate a gas or may be sufficient to provide the necessary reactionenergy for the combination of multiple inflationary reactants to form agas. The at least one reactant may include sodium carbonate and the gasmay include carbon dioxide.

In another embodiment, inflation of the volume-occupying subcomponent isactuated by an externally applied magnetic field. For example, followingingestion of the device to the stomach, a magnetic field, introducedinto the vicinity of the device, can cause a solenoid to close which inturn closes a circuit configured to generate heat when in a closedstate. The generated heat in turn heats a temperature sensitive sealingelement incorporated in the barrier separating the inflation agents.Upon achieving a predetermined temperature, the temperature sensitivesealing element is disrupted or breached and the inflation agents mix,thereby inflating the volume-occupying subcomponent. Alternatively, thegenerated heat may be sufficient to heat at least one reactant which inturn may be sufficient to generate a gas or may be sufficient to providethe necessary reaction energy for the combination of multipleinflationary reactants to form gas.

As a further example, the device may contain a pump that is actuated bypulsatile magnetic energy applied externally and that pumps acid orother fluids in the stomach into the volume-occupying subcomponent andwhich react with an inflation agent (such as carbonate) inside of thevolume-occupying subcomponent causing the volume-occupying subcomponentto inflate. Such actuation may be by means of a voltageelectromagnetically induced by means of a conducting wire forming aclosed loop connected to such pump. As a further example, the barrierseparating inflation agents may contain a magnet, metal or othermagnetophilic substance that, upon external application of a magneticfield, is disrupted or otherwise moved sufficiently to allow a breakageor opening in the barrier sufficient for the inflation agents to mix,thereby inflating the volume-occupying subcomponent. FIGS. 10A and 10Billustrate another example in which the barrier 152 between inflationagents may contain a valve or valves 154 (such as a spool valve) that,upon external application of a magnetic field, are opened to allow theinflation agents to mix, thereby inflating the volume-occupyingsubcomponent.

As a further example, one or more portions of the barrier separatinginflation agents may be stabilized or held together by a magnetic fieldemanating from a magnet in the device that, upon external application ofa degaussing or demagnetizing force, eliminates or reduces the magneticfield sufficiently for one or more portions of the barrier to bedestabilized or otherwise moved sufficiently to allow a breakage oropening in the barrier sufficient for the inflation agents to mix,thereby inflating the volume-occupying subcomponent. Destabilization ormovement of the barrier upon elimination or reduction of the magneticfield may be aided by incorporating one or more spring loaded elementsinto the barrier that are constrained by the magnetic field.

In other embodiments, the barrier separating the inflation reactants maybe a valve that is initially held closed by a spring-loaded element andthat is subsequently released to allow the valve to open therebyallowing the reactants to mix and inflation to commence. The release ofsuch spring-loaded element may be accomplished by any of the methodsdescribed in this application to actuate a mechanical movement orbreakage in the device.

In other embodiments, inflation of the volume-occupying subcomponent maybe actuated by emission of a gas within the volume-occupyingsubcomponent that is generated via an oxidation-reduction reaction. Forexample, oxygen and hydrogen gas may be generated to expand thevolume-occupying subcomponent by electrolyzing a water subcomponentwithin the volume-occupying subcomponent using stainless steelelectrodes. As a further example, the volume-occupying subcomponent maybe inflated by the emission of oxygen gas generated by anelectricity-actuated oxidation-reduction reaction between two differentmetals, where one metal contains an oxide. As a further example, oxalicacid may be electrolyzed. An electrical current to actuate the reactionexamples described above may be generated by any of the means forgenerating such current described elsewhere in this application.

Means for generating electricity or heat to actuate any of the inflationmechanisms described in this application may also include incorporationof a miniature battery (e.g. a button cell) in the device, which may,for example, be activated prior to device delivery or by an external RFor magnetic signal.

Heat or electricity may also be generated by a source external to thedevice and may be transmitted to the device via a tube or stringattached to the device at its distal end and attached to the externalsource at its proximal end. Such tube or string may be released by meansof an electric signal or by any of the means for releasing a tube orstring attached to the device described in the “Inflation Subcomponents”and “Deflation Subcomponents” sections of this application, and, inaddition, may perform any of the tube or string functions described inthe “Inflation Subcomponents” and “Deflation Subcomponents” sections ofthis application.

In another embodiment, an intragastric volume-occupying subcomponent isengineered with a sealed container inside of it, with such containercontaining a mixture of one or more compressed gases and with inflationachieved by the release of gas from this container. Alternatively, thevolume-occupying subcomponent may be engineered in inflated form withthe desired amount of gas inside of it and compressed inside a containersufficiently small to be administered to the patient. Such compressedgas or mixture of gases may include, but are not limited to, one or moreof the following: carbon dioxide, oxygen, nitrogen, and argon. Releaseof gas (in the case of the invention embodiment where a gas container isengineered inside of the volume-occupying subcomponent) or expansion ofthe volume-occupying subcomponent (in the case of the inventionembodiment where a volume-occupying subcomponent filled with the desiredamount of gas is compressed into a delivery container) may be achievedby degradation or destruction of all or a part of the container unitcontaining the gas. Such degradation or destruction may be achieved byany of the means described above as example methods to destroy amechanical barrier between reactants. For example, all or part of thecontainer may be composed of a polysaccharide or polymer structure.

It has been hypothesized that in order to produce the desired feeling ofsatiety in a patient, a portion of the intragastric volume-occupyingsubcomponent must settle within or below the surface of the stomachfluids. It may therefore be advantageous to incorporate a weight into oron the intragastric volume-occupying subcomponent. To this end, incertain additional preferred embodiments, the inflation subcomponent maybe formed so as to also incorporate or otherwise perform a weightingfunction.

For example, in embodiments employing multiple agents or chemicalcomponents which react with one another to inflate the volume-occupyingsubcomponent, the proportions and amounts of each agent may bemanipulated such that the inflation reaction stops prior to exhaustionof all of one of the agents. The remaining quantity of agent willthereby function as a weight in the volume-occupying subcomponent.Alternatively, various other elements of the inflation subcomponent maybe designed to ultimately serve as a weight, e.g. the capsule or otherretaining element that otherwise serves to separate the reactive agentsmay also provide a weighting function after inflation. Alternatively,one or more solids or liquids produced as reaction byproducts may serveto weigh or orient the volume-occupying subcomponent. As illustrated inFIGS. 11A and B, one manner in which remaining reactants and/or reactantbyproducts may be caused to weigh or orient the volume-occupyingsubcomponent 400 comprises engineering all or part of the container 132holding the reactants to be at least partially solid and/or liquidimpermeable, for example engineering the container to function as afilter. In this manner the solid and/or liquid reactants and/orbyproducts are at least partially confined in the container 132,resulting in the container 132 maintaining its weight sufficiently toinfluence the orientation of the volume-occupying subcomponent 400. Forexample, tiny holes may be made in the reactant container 132 (by meansof a laser or other apparatus) to make the container 132 at leastpartially solid impermeable or such container may be designed to be gaspermeable only. In addition, the reactant container 132 may also serveto keep inflation reactants in close proximity to facilitate theirmixing for the generation of gas and the inflation of thevolume-occupying subcomponent 400.

As a further example, the volume-occupying subcomponent may be formed ofa shape-memory or thermo-elastic polymer designed to assume avolume-occupying shape when in its natural, low energy state. Such avolume-occupying subcomponent may initially assume a restricted orconstrained form, of a size and shape for ingestion by a patient whilecausing minimal discomfort, through packaging of the subcomponent into adissolvable or biodegradable material or other container. Once theshape-memory volume-occupying subcomponent enters the stomach, thechemical or temperature environment of the stomach causes therestrictive element to break or disintegrate, by dissolution,degradation or other means, allowing the volume-occupying subcomponentto expand to its natural state. Means for restricting such shape-memoryvolume-occupying subcomponent include, but are not limited to, apolysaccharide capsule. Devices according to the present embodiment may,but need not necessarily employ a cover or sheath. When employed, suchcover or sheath may function to create an internal cavity within thedevice that is isolated from the exterior environment and/or contents ofthe stomach. Possible thermo-elastic or memory shaped polymers for theabove embodiments include latex, silicon, polyurethane, ethylene vinylacetate (EVA) and ethylene vinyl alcohol (EVOH).

As a further example, the volume-occupying subcomponent may be convertedinto its expanded state by the unfolding and/or expansion of a metalframe. Such frame may be formed from a memory metal, such as Nitinol,that is manufactured and treated to assume a configuration small enoughto fit within the device in delivery form, and to transition to theshape of an expanded frame for the volume-occupying subcomponent at atemperature at or below body temperature, e.g., such temperaturemediated expansion acts to deploy the volume-occupying subcomponent toits expanded state. In the case of a Nitinol frame, transition wouldoccur at Nitinol's transition temperature which is modifiable by methodswell known in the art. Devices according to the preferred embodimentsmay, but need not necessarily employ a cover or sheath. When employed,such cover or sheath may function to create an internal cavity withinthe device that is isolated from the exterior environment and/orcontents of the stomach. In order to keep the frame in its smallconfiguration prior to delivery, it may be necessary to store the deviceat a temperature below room temperature. Alternatively, the frame may bemechanically constrained following its manufacture/treating to maintainits small configuration, and the degradation/disintegration/disruptionof such constraint may act as the trigger for expansion of the frame.Potential means for actuating the degradation/disintegration/disruptionof such constraint may include any of the means described above fordegradation/disintegration/disruption of a barrier between two chemicalagents.

In certain embodiments, as illustrated in FIGS. 12-14, it may also beadvantageous for the volume-occupying subcomponent to inflate graduallyor in several steps over time. For example, if gas escapes thevolume-occupying subcomponent prior to the desired deflation time, itwould be beneficial for the device to reinflate in order to preserve itin its expanded state. To this end, in certain additional preferredembodiments, the volume-occupying subcomponent may contain one or moreinflation subcomponents 100 that cause the volume-occupying subcomponentto inflate gradually or in steps over time. For example, the chemicalcomponents which react with one another to inflate with thevolume-occupying subcomponent may be separated in several compartments134 such that they will react gradually or in steps over time. Forexample, as illustrated in FIGS. 12-14, solid reactants 120 and liquid110 may be separated by barriers 160 designed to degrade at differenttimes. As a further example, a first barrier 160 may be designed todegrade several minutes following activation of the device while otherbarriers 160 may be designed to degrade over the course of days, weeksor months. Such degradable barriers 160 may be composed of anybiodegradable or dissolvable material such as polyacetals or polyketals,with the degradation properties of the barrier 160 determined byaltering the composition thereof. The commencement of the barrier 160degradation process may be initiated by any of the trigger mechanismsdescribed herein. Another way to achieve gradual inflation would be forone of the gas generating reactants to be produced gradually by thedegradation of a precursor over time (e.g. over hours, days, weeks ormonths). For example, a polymer such as polylactic glycolic acid (PLGA)may be degraded over time to produce acid byproducts that react withanother reactant contained in the volume-occupying subcomponent togenerate gas. The commencement of the precursor degradation process maybe initiated by any of the trigger mechanisms described herein.

In other embodiments, it may be desirable that once the delivered devicereaches the stomach, the volume-occupying subcomponent inflates quicklyto a desired size in order to reduce the danger of the volume-occupyingsubcomponent passing through the pyloric sphincter following delivery.To achieve such a rapid inflation, one of the inflation agents, e.g.bicarbonate, may be deployed in such a manner so as to maximize itssurface area. Accordingly, upon mixing of the inflation agents, agreater amount of gas may be generated at the beginning of the reaction,resulting in a more rapid expansion of the volume-occupying subcomponentearlier following delivery. Similarly, it may be advantageous for theinflationary reactants to be engineered such that a reaction betweensmall portions of the reactants occurs initially to help to catalyze alarger reaction between the remaining reactants. Such initial smallerreaction may also be used to cause an initial expansion of the device todislocate or move other components within the device into a statenecessary or desirable for inflation or for the device's inflated state.For example, the reactants may be constructed such that, upon initiationof the inflation step, citric acid first comes into contact with a smallconcentration of carbonate, triggering an initial reaction that helps tomix the remaining reactants to initiate a larger reaction. FIG. 42illustrates an embodiment of the device designed to provide for aninitial smaller inflationary reaction that helps to catalyze asubsequent larger inflationary reaction and to initiate the movement ofother components within the device to positions necessary or desirablefor inflation or the device's inflated state. Alternatively, a reagentmay be deployed so as to have an initially rapid rate of reaction and asubsequently decreasing rate. Such a variable rate of reaction andthereby inflation of the volume-occupying subcomponent may be achievedby deploying, for example, a solid reagent in the form of a compressedball.

In another embodiment, illustrated in FIGS. 15A and 15B, the device maycontain a wicking element 180 in proximity to the gas generatingreactants that, once in contact with a liquid reactant, serve as amedium for the liquid reactant to travel on in order to contact thesolid reactant to initiate the inflation reaction. FIG. 15A shows across-sectional view of the device 10 in the delivery state, and FIG.15B shows a cross-sectional view the device 10 in the deployed orexpanded state. Such an embodiment would be advantageous because itwould facilitate the chemical reaction by facilitating contact betweenreactants, and it may also enable a more complete reaction byfacilitating contact between a higher proportion of the reactants thancould be accomplished in the absence of the wicking element 180. Forexample, the wicking element 180 may be composed of a hydrophilicmaterial, such as paper, that allows a liquid reactant to travel to asolid reactant by means of capillary action. In another embodiment, thewicking element 180 may contain or be implanted with the solid reactanton all or a part of its surface.

It may also be advantageous for the device to contain subcomponents thataid in the mixing of inflation agents to increase the rate and/orcompletion of their reaction in order to increase the rate or degree ofvolume-occupying subcomponent inflation. This would be beneficial, forexample, because it would allow the device to be engineered to contain alesser quantity of reactants so that it can be configured to assume asmaller size, facilitating its swallowability and passage to thestomach. For example, methods of generating heat in the device using anexternal RF or magnet field source similar to those described can beused to heat the inflation agents to increase their mixing. For example,methods of generating electrical energy in the device using an externalRF, magnet field, or pulsatile magnetic energy source similar to thosedescribed above can be used to power a mixing element proximate to theinflation agents. Such mixing element may be, for example, a pump. Asanother example, such mixing element may be one or more magnetophilicagents whose movement is stimulated by an external magnetic field ormagnet pulses. In another embodiment, mixing of the inflation elementsmay be achieved by an external lithotripter emitting high-intensityacoustic pulses towards such elements. Any of the foregoing methods usedto mix inflation elements may also be used to increase their associationso as to enhance the reaction between them.

In another example, the barrier separating the chemical inflation agentsis susceptible to disruption by lithotripsy techniques. Lithotripter,externally-applied, focused, high-intensity acoustic pulses, may beapplied to the barrier to disrupt or otherwise breach the elements andthereby allow the chemical agents to mix and the balloon to inflate. Thebarrier may also be comprised of materials that resonate at a certainfrequency such that when such frequency is applied using an externalsource such frequency will cause the barrier materials to oscillatesufficiently to disrupt or otherwise breach the elements and therebyallow the chemical agents to mix and the balloon to inflate. The rangefor such frequency would include the infrasonic, acoustic and ultrasonicfrequency ranges. Materials that may be disrupted by lithotripsy or thatmay be designed to resonate at a certain frequency may include glass,ceramics, calcium, alkaline composites and/or brittle materials.DEFLATION SUBCOMPONENTS

According to preferred embodiments, deflation of the volume-occupyingsubcomponent is achieved without resort to invasive procedures.Deflation subcomponents may function as a programmed time baseddeflation in which, after a certain period of time has lapsed sincedeployment or delivery of the device, the device self-deflates, withoutexternal stimulus. Alternatively, deflation may be externally triggeredby a stimulus applied by the physician. Devices according to the presentinvention may employ a combination of the deflation subcomponents toprovide greater ease of operation and greater control and safety of thedevice.

In a preferred embodiment, the volume-occupying subcomponent 400 maycontain a biodegradable or dissolvable head 202 that upon degradationallows fluid to escape and the volume-occupying subcomponent 400 todeflate. The head 202 may be constructed in such a manner thatdisintegration of the head 202 materials from the volume-occupyingsubcomponent 400 accelerates after a degree of degradation has occurred.For example, as illustrated in FIGS. 16A and 16B, a first portion 204 ofthe head 202 may be designed to degrade faster than a second portion 206of head 202 with the first portion 204 stabilizing the second portion206 of the head 202 such that when the first portion 204 degrades,second portion 206 destabilize and is released from the head 202,thereby accelerating the deflation process. Examples of head 202 designscan include outer portions held together by a faster degradingcenterpiece, a head 202 with a slower degrading outer half and fasterdegrading inner half. An inner portion may also be partially heldtogether by a water soluble adhesive that, upon degradation of the outerhalf of the head, becomes in contact with the contents of the stomach,resulting in accelerated disintegration of the inner half of the head.FIGS. 16A, 16B also illustrate further embodiments in which thedeflation subcomponent 200 may contain more than one head 202 throughwhich fluid is released upon deflation.

In certain preferred embodiments, the degradable head may containmaterials that are degraded by enzymes that are normally present in thestomach, such as pepsin or other proteases.

Alternatively, as illustrated in FIGS. 17A and 17B, the head 202 mayincorporate a tension element 210, such as a spring, a degradable link212, and one or more plug elements 214. The degradable link 212 servesto secure the tension element 210 around plug element 214 such that,upon degradation of the degradable link 212, tension element 210releases all or part of plug element 214 from the head 202, therebyallowing for the escape of fluid from the volume-occupying subcomponent400.

In a preferred embodiment, deflation subcomponents 200 may be employedthat are susceptible to disruption by lithotripsy techniques. Forexample, as illustrated in FIGS. 18 and 19, the deflation subcomponent200 may incorporate a trigger element 220 such as a small head, vial, orglass membrane in the wall of the volume-occupying subcomponent 400.Lithotripter, externally-applied, focused, high-intensity acousticpulses, may be applied to the trigger element 220 to disrupt orotherwise breach the elements and thereby allow the inflation fluid toescape and the volume-occupying subcomponent 400 to deflate. The triggerelement 200 may also be comprised of materials that resonate at acertain frequency such that when such frequency is applied using anexternal source such frequency will cause the materials to oscillatesufficiently to disrupt or otherwise breach the elements and therebyallow the inflation fluid to escape and the volume-occupyingsubcomponent 400 to deflate. The range for such frequency would includethe infrasonic, acoustic and ultrasonic frequency ranges. Materials thatmay be disrupted by lithotripsy or that may be designed to resonate at acertain frequency may include glass, ceramics, calcium, alkalinecomposites and/or brittle materials.

In another preferred embodiment, the deflation subcomponent employs anexternally applied magnetic field. For example, the deflationsubcomponent may be configured such that a magnet field, introduced intothe vicinity of the deployed device, causes a solenoid to close which inturn closes a circuit configured to generate heat when in a closedstate. The generated heat in turn heats a temperature sensitive sealingelement incorporated in the volume-occupying subcomponent wall. Uponachieving a predetermined temperature, the temperature sensitive sealingelement is disrupted or breached and the fluid inside thevolume-occupying subcomponent escapes, thereby deflating thevolume-occupying subcomponent. Alternatively, a microfilm may beactivated by the magnetic field and used to heat and disrupt thevolume-occupying subcomponent.

As a further example, the deployed device may contain a pump that isactuated by pulsatile magnetic energy applied externally and that pumpsfluid out of the volume-occupying subcomponent causing thevolume-occupying subcomponent to deflate. Such actuation may be by meansof a voltage electromagnetically induced by a conducting wire forming aclosed loop connected to such pump.

As a further example, the wall or head of the volume-occupyingsubcomponent may contain a magnet, metal or other magnetophilicsubstance that, upon external application of a magnetic field, isdisrupted or otherwise moved sufficiently to allow a breakage or openingin the volume-occupying subcomponent or head of the volume-occupyingsubcomponent sufficient for fluid inside of the volume-occupyingsubcomponent to escape, thereby deflating the volume-occupyingsubcomponent.

FIGS. 20A-D illustrate a further example in which the head 202 of thedeflation subcomponent 200 may contain one or more valves 230, such asspool valves, that, upon external application of a magnetic field, isopened to allow fluid inside of the volume-occupying subcomponent 400 toescape, thereby deflating the volume-occupying subcomponent 400. FIG.20A illustrates a top-view of the head 202 in which the valves 230 areclosed. FIG. 20B illustrates a top-view of the head 202 in which thevalves 230 are open. FIG. 20C illustrates a cross-section view of thehead 202 in which the valves 230 are closed. FIG. 20C illustrates across-section view of the head 202 in which the valves 230 are open andthe fluid inside the volume-occupying subcomponent 400 is flowing outfrom the volume-occupying subcomponent 400.

As a further example, one or more portions of the head of thevolume-occupying subcomponent may be stabilized or held together by amagnetic field emanating from a magnet in the volume-occupyingsubcomponent. Upon application of an external degaussing ordemagnetizing force, the magnetic field is sufficiently reduced oreliminated so as one or more portions of the head are destabilized toallow a breakage or opening in the volume-occupying subcomponent or headof the volume-occupying subcomponent. Destabilization or movement of thehead upon elimination or reduction of the magnetic field may be aided byincorporating one or more spring loaded elements into the head that areconstrained by the magnetic field.

A further embodiment provides for the deflation to occur by productionof magnetic field gradients which will melt a hole in the side of thevolume-occupying subcomponent sufficient to release the inflation fluid.A magnetic field can be created by current flowing through the coil of arelay which would alter micro switch contacts.

Alternatively, the device may employ a magnetized sealing element withinor on the volume-occupying subcomponent. For example, a spring loadedsealing element may be incorporated into the wall of thevolume-occupying subcomponent. Application of an external magnet fieldto the vicinity of the device within the patient will counter the springloaded sealing element and thereby deflate the device.

In certain alternative preferred embodiments, the deflation subcomponentutilizes a chemical-based technique. For example, after the device hasbeen deployed for a specific time period within the patient, the patientwill ingest a substance designed to target and degrade the material fromwhich the volume-occupying subcomponent is formed or a sealing elementincorporated within the volume-occupying subcomponent. The degradingsubstance may be ingested by the patient in the form of a pill, capsule,or liquid. Preferably, the degrading substance is operable to causedeflation within a predictable, short period of time between 0 and 24hours following administration of the degrading substance. For example,the all or part of the volume-occupying subcomponent wall or head may becomposed of a polymer that is degraded by one or more specific enzymesor bacteria, with the degrading substance to be administered being theapplicable enzyme or bacteria.

One embodiment of the deflation subcomponent utilizes a remotelyadjustable implantable microchip which would open and close a valvecontrolling fluid within the volume-occupying subcomponent. This valvecan also be opened using an electrokinetic pump actuation or by pressureactivation.

In yet another embodiment, the deflation subcomponent is engineered witha power source and radiofrequency transformer such that an externalwireless RF signal is able to be transformed into electric energy andcreate a voltage difference to deflate the volume-occupyingsubcomponent. For example, deflation may be achieved in this manner bymeans of a polymer microfilm adjacent to the wall of thevolume-occupying subcomponent or the materials in the head of thevolume-occupying subcomponent, the electric energy triggered by the RFsignal causing such microfilm to melt a part of the wall or suchmaterials sufficiently to cause a breach in the volume-occupyingsubcomponent to allow deflation. The RF signal may be received by meansof an antenna adjacent to the power source. Alternatively, no powersource may be required for the conversion of the RF signal to electricenergy, for example by employing “ping and listen” technology.

In another embodiment, an RF signal may be employed to power a pump thatcauses deflation by pumping a fluid out of the volume-occupyingsubcomponent. Alternatively, an RF signal may be used to open a valve torelease fluid from the volume-occupying subcomponent and thereby causedeflation.

In a further embodiment, the deflation subcomponent employs alight-absorbing compound such as a chromophore incorporated into avalve. Application of an appropriate light source functions to modifythe valve composition in vivo. The modification results in a heating ofthe valve to a temperature at which the material ruptures, and therebydeflates. Light exposure to the barrier following administration of thedevice to the patient may be accomplished by exposing the barrier to alight source external to the volume-occupying subcomponent, e.g. byinserting an endoscope or wand with a light source at its end orallydown the gastrointestinal tract and which then emits light at the valve.

In other embodiments, deflation of the volume-occupying subcomponent maybe achieved, in part or entirely, through a change in the internalpressure in the volume-occupying subcomponent. For example, thevolume-occupying subcomponent's internal pressure may activate apneumatic valve in the volume-occupying subcomponent so as to open andrelease a fluid and deflate.

It may be advantageous to design the device in ways that improve therate of deflation of the volume-occupying subcomponent or cause it todeflate more completely. To this end, as illustrated in FIGS. 21A and B,all or part of the volume-occupying subcomponent 400 may incorporate aelastomeric material (silicon, for example) that forms a sheath or wall240 that applies a contracting force on the volume-occupyingsubcomponent 400 and facilitates deflation once the volume-occupyingsubcomponent 400 has been breached. FIG. 21A illustrates avolume-occupying subcomponent 400 in the inflated or deployed state thatemploys a sheath wall 240. The contraction force applied by sheath orwall 240 may be applied in an asymmetric manner to the volume-occupyingsubcomponent 400. For example, as illustrated in FIG. 21B, thecontraction force may act primarily along a longitudinal axis such thatthe deflated volume-occupying subcomponent 400 has a first dimensionthat is greater than a second dimension.

It may be advantageous for the volume-occupying subcomponent to containa duct valve or other type of valve that allows fluid to exit thevolume-occupying subcomponent upon initiation of the deflation step butthat permits little or no fluid to enter or flow back into thesubcomponent.

Delivery Subcomponents

In the delivery state, devices according to the preferred embodimentsemploy a configuration that facilitates swallowing of the device whileproducing minimal discomfort to the patient. Preferably, thevolume-occupying subcomponent is in a compressed configuration and otherdevice subcomponents are sized so that the entire device may conform tothe general shape of a capsule. As illustrated in FIGS. 2A-5B, in thedelivery state, the device 10 may be configured in any number of shapes,including the following: round (see FIGS. 3A and B), oblong (see FIGS.2A and B), oval (see FIGS. 5A and B), suppository-shaped,mushroom-shaped, finger-shaped, bullet-shaped or torpedo-shaped (seeFIGS. 4A and B). A bullet-shaped capsule, for example, may contain thecontents of the volume-occupying subcomponent more efficiently.

In a preferred embodiment, the device is fitted into a standard sizedgelatin capsule. The capsule may be formed of a material that has a knowrate of degradation such that the device will not be released from thecapsule or otherwise deployed prior to entry into the stomach. Forexample, the capsule materials may include one or more polysaccharideand/or one or more polyhydric alcohols.

Alternatively, the device, in its delivery state, may be coated in asubstance that confines the device in its delivery state while alsofacilitating swallowing. The coating may be applied by a dipping,sputtering, vapor deposition, or spraying process which may be conductedat an ambient or positive pressure.

In certain preferred embodiments, the encapsulated or coated device islubricated or otherwise treated so as to facilitate swallowing. Forexample, the encapsulated or coated device may be wetted, heated, orcooled, prior to swallowing by the patient. Alternatively, theencapsulated or coated device may be dipped in a viscous substance thatwill serve to lubricate the device's passage through the esophagus.Examples of possible coatings would be any substances with lubriciousand/or hydrophilic properties and include glycerine,polyvinylpyrrolidone (PVP), petroleum jelly, aloe vera, silicon-basedmaterials (e.g. Dow 360) and tetrafluoroethylene (TFE). The coating mayalso be applied by a sputtering, vapor deposition or spraying process.

In additional embodiments the coating or capsule is impregnated ortreated with one or more local anesthetics or analgesics to easeswallowing. Such anesthetics may include anesthetics in the amino amidegroup, such as articaine, lidocaine and trimecaine, and anesthetics inthe amino ester group, such as benzocaine, procaine and tetracaine. Suchanalgesics may include chloraseptic.

In certain embodiments, the capsule may be weighted at a certain end inorder for it to be oriented appropriately when it is administered, as ittravels down the esophagus, and/or when it is in the stomach. Theweighting components may include polymer materials or inflationreactants.

It may advantageous for an administrator of the device to use a deliverytool 310 for delivering the device 10 to the mouth or facilitating itspassage through the esophagus in the optimal orientation. A deliverytool 310 may enable the device administrator to inject the device 10with one or more inflation agents as the device 10 is being administeredto the patient. In a preferred embodiment, such injection may beaccomplished in the same mechanical action(s) of the administrator thatare employed to release the device 10 from the delivery tool 310 intothe mouth or esophagus. For example, with reference to FIG. 22A, thedelivery tool 310 may include a plunger 312, a reservoir 318 having aliquid 110, and an injection needle 320. As shown in FIGS. 22B and C,the administrator pushes the plunger 312 which, either in sequence orapproximately simultaneously, forces the injection needle 320 into thedevice 10 and thereby injects the liquid 110 contained in reservoir 318into the device 10. Subsequent application of force to the plunger 312pushes the device out of the delivery tool 310 and into the desiredlocation within the patient. Furthermore, the delivery tool 310 may alsoinclude a subcomponent that administers an anesthetic or lubricant intothe patient's mouth or esophagus to ease the swallowability of thedevice.

It may be advantageous for the administrator of the device to have ameans of retrieving the device if it were to get stuck in the patient'sesophagus following administration. Accordingly, certain embodiments ofthe device in its delivery state may include a string with one endattached to the device and with the other end able to be held by theadministrator. The string may be attached to the device firmly enough toallow the administrator to exert enough force on the string to pull thedevice from the patient's esophagus if it is lodged there. The stringwould be long enough to allow the device to reach the patient's stomachwhile still having the other end held by the administrator. The stringmay be attached to the device in such a manner that it detaches withinminutes after the device is in the stomach. For example, the string maybe attached to the device by means of a water or stomach acid solubleadhesive.

Volume-Occupying Subcomponent

The volume-occupying subcomponent of the preferred embodiments isgenerally formed of a flexible material forming a wall which defines anexterior surface and an interior cavity. Various of the above-describedsubcomponents may be either incorporated into the wall or interiorcavity of the volume-occupying subcomponent. FIGS. 23-32 are perspectiveviews of various volume-occupying subcomponents 400. As shown,volume-occupying subcomponent 400 will vary in size and shape accordingto the patient's internal dimensions and the desired outcome. Thevolume-occupying subcomponent 400 may be engineered to besemi-compliant, allowing the volume-occupying subcomponent 400 tostretch or expand with increases in pressure and/or temperature.

It may advantageous for the volume-occupying subcomponent 400 to orientitself in a certain position and/or in a certain area of the stomach inorder, for example, to induce satiety by interacting with a certain areain the stomach or to avoid interacting with a certain area of thestomach that would cause nausea. Accordingly, the volume-occupyingsubcomponent 400 may be designed in one or more ways to achieve adesired orientation/position. For example, the volume-occupyingsubcomponent 400 may contain a second component, such as a ring, thatinflates around all or a portion of the volume-occupying subcomponent400 and that facilitates the desired orientation/position of thevolume-occupying subcomponent 400.

Alternatively, the volume-occupying subcomponent 400 may be constructedto be donut-shaped, see FIGS. 26 and 34, with a hole 420 in the middleof it, and may be weighted and shaped in such a way that it orients inthe stomach to cover all or part of the pyloric sphincter, similar to acheck valve. The hole 420 in the middle of the volume-occupyingsubcomponent 400 would then serve as the primary passage for thecontents of the stomach to enter the small intestine, limiting thepassage of food out of the stomach and inducing satiety by reducinggastric emptying. Volume-occupying subcomponent 400 may be manufacturedwith different-sized donut-holes according to the degree that gastricemptying is desired to be reduced. Delivery, inflation and deflation ofthe volume-occupying subcomponent 400 may be accomplished by any of themethods described above.

It would be advantageous for the volume-occupying subcomponent wall tobe both high in strength and thin. Accordingly, the volume-occupyingsubcomponent wall materials may be manufactured with a biaxialorientation that imparts a high modulus value to the volume-occupyingsubcomponent.

In one embodiment, a device according to the present invention isconstructed of a polymeric substance such as polyurethane, polyethyleneterephthalate, polyethylene naphthalate, polyvinyl chloride (PVC), Nylon6, Nylon 12, or polyether block amide (PEBA). The volume-occupyingsubcomponent may be coated with one or more layers of substances thataid in achieving greater gas-barrier characteristics, such as athermoplastic substance.

Preferably, the gas-barrier materials have a low permeability to carbondioxide or other fluids that may be used to inflate the volume-occupyingsubcomponent. The barrier layers should have good adherence to the basematerial. Preferred barrier coating materials include biocompatiblepoly(hydroxyamino ethers), polyethylene naphthalate, polyvinylidenechloride (PVDC), saran, ethylene vinyl alcohol copolymers, polyvinylacetate, silicon oxide (SiOx), acrylonitrile copolymers or copolymers ofterephthalic acid and isophthalic acid with ethylene glycol and at leastone diol. Alternative gas-barrier materials may includepolyamine-polyepoxides. These materials are commonly acquired as asolvent or aqueous based thermosetting composition and are generallyspray-coated onto a preform and then heat-cured to form the finishedbarrier coating. Alternative gas-barrier materials which may be appliedas coatings to the volume-occupying subcomponent include metals such assilver or aluminum. Other materials that may be used to improve the gasimpermeability of the volume-occupying subcomponent include, but are notlimited to, gold or any noble metal, PET coated with saran, conformalcoatings and the like, as listed, for example, in Table 1.

In certain preferred embodiments, the volume-occupying subcomponent isinjection, blow or rotational molded. Either immediately following suchmolding, or after a period of curing, the gas-barrier coating may beapplied.

In another embodiment, the intragastric volume-occupying subcomponent isformed using a Mylar polyester film coating silver, aluminum orkelvalite as a metallicized surface, to improve the gas impermeabilityof the volume-occupying subcomponent.

In the event that the volume-occupying subcomponent's wall is composedof multiple layers of materials, it may be necessary to use certainsubstances or methods to connect, attach or hold together such multiplelayers. Such substances can include a solvent or an ether-basedadhesive. Such multiple layers may also be heat-bonded together. Oncesuch layers are attached together to form (for example) a sheet ofmaterial to be made into a volume-occupying subcomponent, it may also benecessary to apply additional treatment steps to such material to allowit to seal together (for example, by application of a certain degree ofheat and pressure) in order to be made into a volume-occupyingsubcomponent. Accordingly, it may be advantageous to include as anadditional layer in the volume-occupying subcomponent certain materialsthat seal. For example, a volume-occupying subcomponent comprised of acombination of PET and SiOx layers, which impart favorable mechanicaland gas impermeability characteristics to the volume-occupyingsubcomponent, may be sealed by including a layer of sealablepolyethylene in such volume-occupying subcomponent.

According to another embodiment of the preferred embodiments, thefunctionality of the volume-occupying subcomponent and the deflationcomponent is combined either in part or in whole. For example, thevolume-occupying subcomponent may be formed of a substance that isdegraded within the stomach over a desired period of time. Once thedegradation process has formed a breach in the wall of thevolume-occupying subcomponent, the volume-occupying subcomponentdeflates, continues to degrade and passes through the remainder of thedigestive tract.

Preferably, an automated process is employed that takes a fullyconstructed volume-occupying subcomponent, evacuates all of the airwithin the interior cavity and folds or compresses the volume-occupyingsubcomponent into the desired delivery state. For example, theevacuation of air from the volume-occupying subcomponent may be actuatedby vacuum or mechanical pressure (e.g. rolling the volume-occupyingsubcomponent). In certain embodiments, it is desirable to minimize thenumber of creases produced in the volume-occupying subcomponent when inthe delivery state.

In another embodiment, illustrated in FIG. 33, deflation of thevolume-occupying subcomponent 400 may be achieved through one or moreinjection site 250 within the wall of the volume-occupying subcomponentmay be used. For example, two self-sealing injection sites can beincorporated at opposite sides of the volume-occupying subcomponent, seeFIG. 33. The volume-occupying subcomponent may be positioned within afixture that employs two small-gauge needles to evacuate the air fromthe volume-occupying subcomponent.

In one embodiment, the self-sealing injection sites may further be usedto insert chemical elements of the inflation subcomponent into theinterior of the volume-occupying subcomponent. After injection of thechemical elements into the volume-occupying subcomponent, the sameneedles may be used to perform evacuation of the volume-occupyingsubcomponent.

It may be desirable that the volume-occupying subcomponent is packedinto the delivery state under, for example, a negative vacuum pressureor under a positive external pressure.

The volume-occupying subcomponent wall materials may also be engineeredto, once they are initially punctured or torn, tear relatively easilyfrom the point of such puncture or tear. Such properties would, forexample, be advantageous if deflation of the volume-occupyingsubcomponent were initiated by a tearing or puncturing of thevolume-occupying subcomponent wall, since such initial tear or puncturemay then increase in scope, hastening and/or maximizing the deflationprocess.

The volume-occupying subcomponent may also be coated by a lubricioussubstance that facilitates its passage out of the body following itsdeflation. Examples of possible coatings would be any substances withlubricious and/or hydrophilic properties and include glycerine,polyvinylpyrrolidone (PVP), petroleum jelly, aloe vera, silicon-basedmaterials (e.g. Dow 360) and tetrafluoroethylene (TFE). The coating maybe applied by a dipping, sputtering, vapor deposition or sprayingprocess which may be conducted at an ambient or positive pressure.

Tracking and Visualization Subcomponent

It may also be beneficial to implement tracking and visualizationfunctionality into devices according to the present inventions. Due tothe non-invasive nature of the present device, physicians may desire todetermine, or confirm, the location and orientation of the device priorto inflation or during the course of treatment.

In one embodiment, the volume-occupying subcomponent incorporates abarium sulfate or other radioopaque marker, e.g., a metallic substance.The marker may be implemented so as to form an identifiable geometricpattern on the inflated volume-occupying subcomponent when imaged orotherwise viewed on x-ray or other visualization equipment. For example,the marker may form a circular stripe at the equator and/or a stripearound each pole of the volume-occupying subcomponent. As shown in FIG.35, the markers 510 form expanded circles and are positioned relativelyfar apart, indicating that the volume-occupying subcomponent 400 is inthe deployed or inflated state. The approximately horizontal position ofthe markers 510 indicates that the axes of the volume-occupyingsubcomponent 400 that are bounded by the markers 510 are approximatelyparallel with respect to the illustrated reference line 520. In FIG. 36,the markers 510 form condensed circles positioned relatively closetogether, indicating that the volume-occupying subcomponent 400 is in adeflated state. In FIG. 37, the distance between the markers 510indicates that the volume-occupying subcomponent 400 is inflated, andtheir approximately vertical position indicates that the axis of thevolume-occupying subcomponent 400 that is bounded by the markers 510 isapproximately perpendicular with respect to the illustrated referenceline 520.

Alternatively, the marker may be applied to the volume-occupyingsubcomponent when the volume-occupying subcomponent is in a creased orfolded state such that when the volume-occupying subcomponent is in itsdeflated state the marker appears concentrated when viewed onvisualization equipment, and when the volume-occupying subcomponent isinflated the marker appears less concentrated when viewed onvisualization equipment. Alternatively, the marker may be applied orincorporated into the volume-occupying subcomponent so as to facilitateidentification and location of the various subcomponents of the device,such as a valve, head, or weight. The marker may be printed or paintedonto a surface of the volume-occupying subcomponent or between layers ofthe material forming the volume-occupying subcomponent. Alternatively, ametal coating as described below may be used as a marker to identifyand/or locate the volume-occupying subcomponent. Metal coatings forvisualizing the volume-occupying subcomponent may include silver, gold,tantalum or any noble metal. Alternatively, the marker may be applied toan elastomeric sleeve that covers all or part of the volume-occupyingsubcomponent.

In another embodiment, the volume-occupying subcomponent incorporates asubcomponent that changes mechanically upon inflation of thevolume-occupying subcomponent, which mechanical change can be visualizedusing x-ray or other visualization equipment. For example, a mechanicalportion of the volume-occupying subcomponent containing a visualizationmarker may elongate upon an increase in pressure in the volume-occupyingsubcomponent.

Alternatively, a marker may be formed using a metalized mesh locatedbetween layers of the material from which the volume-occupyingsubcomponent is constructed. The pattern or patterns formed by theimbedded marker will appear when the volume-occupying subcomponent is inan inflated, deployed state.

In another embodiment, other visualization approaches are utilized asposition markers including an infrared LED tag, ultraviolet absorbingcompounds, fluorescent or colored compounds and a metalized strip on thevolume-occupying subcomponent that is positioned in a pattern.

It is envisioned that marker materials may be incorporated into thevolume-occupying subcomponent to facilitate various visualizationtechniques such as, for example, MRI, CT and ultrasound.

The volume-occupying subcomponent may also contain a dye or marker thatis released upon deflation to indicate that the volume-occupyingsubcomponent cavity has been breached. Such dye or marker may, forexample, be apparent in the patient's urine as an indication that thevolume-occupying subcomponent has begun to deflate.

In yet further embodiments, microchips and other components employingelectronic modalities may be used to locate and identify a device.Microchips analogous to those utilized for the identification of petsmay be used to communicate device specific information and itsapproximate location. For example, a Wheatstone or other bridge circuitmay be incorporated into the device and, together with RF “ping andlisten” technology may be used as part of a system to determine thedevice's approximate location and measure and communicate devicespecific information. Such device specific information can includeinternal volume-occupying subcomponent pressure, which can indicate thedegree of inflation of the volume-occupying subcomponent.

In yet further embodiments, mechanical, chemical, visual and othersensors may be included as part of the device to measure, record and/ortransmit information relating to the device and/or the patient'sinternal environment. For example, the device may contain a camera orany of the other imaging and transmission components of a Pillcamdevice. As an additional example, the device may contain sensors thatmeasure, record and/or transmit information relating to stomach pH,stomach pressure, hormone levels, organ health, and organ safety.

Drug Delivery Subcomponent

It is also envisioned that the device of the preferred embodiments mayfurther achieve the objective of delivering and administering variouspharmaceutical therapies and treatments. Pharmaceutical substances maybe incorporated into the material forming the volume-occupyingsubcomponent, into degradable pockets formed on the interior or exteriorsurfaces of the volume-occupying subcomponent, and/or coated on theoutside of the volume-occupying subcomponent. Alternatively oradditionally, pharmaceutical substances may be incorporated into or onone or more of the various other subcomponents of the device.

For example, FIGS. 38A and B illustrate how different drugs, A, B, andC, may be applied in different regions on the surface of thevolume-occupying subcomponent 400. Alternatively, the outside of thevolume-occupying subcomponent may be comprised of a microporous ormeshed exterior designed to facilitate deposition and release of drugmaterials. FIGS. 39A and B show a volume-occupying subcomponent 400containing a mesh or microsphere 610 like surface where drugs may bedeposited or embedded.

In certain embodiments, as seen in FIGS. 40A through 41B, thevolume-occupying subcomponent 400 may contain pharmaceutical substancesin an interior cavity. FIG. 40A shows the volume-occupying subcomponent400 in a deployed or inflated state containing a drug 620 in an interiorvolume of the volume-occupying subcomponent 400. FIG. 40B shows thevolume-occupying subcomponent 400 in a deflated state and the subsequentrelease of the drug 620 from the interior of the volume-occupyingsubcomponent 400. FIG. 41A shows a volume-occupying subcomponent 400containing a drug 620 in a sub-compartment 615 of the volume-occupyingsubcomponent 400 that is adjacent to the head 202. FIG. 41B shows thesubsequent release of drug 620 from the sub-compartment 615. Release ofthe drug 620 from sub-compartment 615 may be achieved by any number ofmeans such as by a pump, valve or head breakage.

Alternatively, the inflation subcomponent may be configured to graduallyrelease pharmaceutical substances as the head component(s) disintegrateor in bulk when the head component separates from the volume-occupyingsubcomponent. For example, a pharmaceutical may be fixed inbiodegradable plug materials and released as such materials degrade inthe stomach. Such substances may be incorporated or implanted into apolymer (e.g. by means of diffusion or hydrolysis) which can be sprayed,sputter coated, vapor deposited or applied in liquid form onto theoutside of the volume-occupying subcomponent.

Furthermore, pharmaceutical substances may also be incorporated into oneor more of the barrier coatings of the volume-occupying subcomponent ora lubricious coating applied to the volume-occupying subcomponent.Release of the drug may, for example, be modulated by diffusion of thedrug from the coating or by degradation of the coating itself, resultingin the release of the drug. The release or diffusion properties of thedrug may be influenced by modifying the characteristics of the polymer,such as by changing the ratio of hydrophobic to hydrophilic molecules inthe composition of the polymer. Release of drug may also be modulated byelectrophoresis actuated by remotely by an external source.

It may be advantageous to treat the volume-occupying subcomponent suchthat its outer layer has antimicrobial properties so that it may treator prevent stomach infections. For example, certain portions of theouter layer of the volume-occupying subcomponent may contain silver. Asa further example, the outer layer of the volume-occupying subcomponentmay be made of a material (such as polyurethane) that allows for iontransfer across of it, with silver materials behind such layer such thatthe silver ions are able to diffuse out of the volume-occupyingsubcomponent or onto its exterior surface.

For example, the volume-occupying subcomponent may be coated with adrug, or combination of drugs, to control stomach acid and othergastrointestinal conditions such as ulcers and GERD. The drugs may, butneed not be selected from the group of drugs including proton pumpinhibitors such as Prilosec, Nexium, Prevacid, Protonix and Aciphex orH₂ receptor antagonists such as Tagamet, Pepcid, Axid, Zantac andRotane.

The volume-occupying subcomponent may be treated with anti-emetics drugor combinations of anti-emetics to control nausea and vomitingincluding, but not limited to, 5HT3 antagonists such as compazine,dolasetron, granisetron, ondansetron, tropisetron, palonosetron ordopamine antagonists such as domperidone, droperidol, haloperidol,chlorpromazine, promethazine, prochlorperazine, metoclopramide,alizapride or antihistamines (H1 receptor antagonists) such ascyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine,hydroxyzine or cannabinoids.

The volume-occupying subcomponent may be coated with drugs orcombinations of drugs to control body weight including serotoninre-uptake inhibitors (e.g., fluoxetine), noradrenergic re-uptakeinhibitors (e.g., phentermine), a serotonin and noradrenergic re-uptakeinhibitor (sibutramine) and an intestinal lipase inhibitor (orlistat),Leptin, amylin, melanocortin-4 receptor agonists, neuropeptide Yantagonists, beta(3) adrenergic agonists and glucagon-like peptide-1agonists and CB1 endocannabinoid receptor antagonists and CNS modulatorsthat mediate appetite and energy expenditure.

The volume-occupying subcomponent may also be coated with drugs orcombinations of drugs to control blood glucose levels including but notlimited to sulfonylureas, meglitinides, nateglinides, biguanides,thiazolidinediones, and alpha-glucose inhibitors.

Example drugs may also include satiety signaling substances orsubstances that modulate hormone levels.

Example drugs may also include laxative agents. Such laxative agents maybe useful in facilitating the passage of the volume-occupyingsubcomponent from the body when it is in its deflated state.

Example drugs may also include substances that modulate gastric emptyingsuch as cholestyramine, or that modulate gastric absorption.

Example drugs may also include analgesics such as acetaminophen, thenon-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylatesand narcotic drugs such as morphine.

Example drugs may also include substances that reduce nicotine and/ortobacco craving such as varenicline, bupropion and nortriptyline.

Example drugs may also include birth control substances such ascombinations of estrogen and progestin, and selective estrogen receptormodulators.

Example drugs may also include antibiotics or other antibacterialsubstances.

Example drugs may also include antacids.

A possible alternative to a coated volume-occupying subcomponent is avolume-occupying subcomponent containing reservoirs that contain thepharmaceutical of interest. For example, the present invention providesa volume-occupying device that could be used as a subcomponent fordelivering drugs to the stomach, possibly including a framework with aplurality of reservoirs and a drug polymer or combination of drugpolymers positioned in the reservoirs. In one embodiment, a plurality ofmicrocapsules on the exterior of said volume-occupying subcomponent,each of said microcapsules carrying a drug or combination of drugs fortreatment with the stomach when said volume-occupying subcomponent, ispositioned and inflated such that the drug or drugs may be released fromsaid microcapsules.

A possible alternative to a coated volume-occupying subcomponent is avolume-occupying subcomponent containing the pharmaceutical of interestin its plug materials. Any of the means to initiate deflation describedabove may be used to modulate erosion or breakage of the plug materialsto initiate release of drug substance.

A possible alternative to a coated volume-occupying subcomponent is avolume-occupying subcomponent containing the pharmaceutical of interestin its creases when it is in is delivery form, with release of the druginitiated by expansion of the volume-occupying subcomponent.

A possible alternative to a coated volume-occupying subcomponent is avolume-occupying subcomponent containing the pharmaceutical of interestin its cavity. Release of the drug may be modulated by a pump that maybe actuated as described above.

The drug delivery components of the volume-occupying subcomponent may bedesigned in such way as to incorporate multiple drugs and to releaseselect drugs upon command. For example, drugs may be layered on top ofone another or adjacent to each other on certain portions of thevolume-occupying subcomponent.

The contents of the following publications, which recite methods ofcontrolled drug delivery are hereby incorporated into this applicationby reference: Langer, R. (1998) “Drug Delivery and Targeting,” Naturevol. 392/Supp, pp. 5-10; Controlled Drug Delivery Systems, Xue Shen Wu,PhD., Technomic Publishing Co, 1996.

Alternatively, the volume-occupying subcomponent may contain asubcomponent that may electro-modulate certain nerves in the stomach(such as the vagus nerve) to induce satiety. Such subcomponent may berecharged inductively by an exterior power source.

Swallowable, Self-Inflating Intragastric Balloon System

A swallowable, self-inflating intragastric balloon system according toselected preferred embodiments includes the following components: aballoon in a deflated and compacted state (“balloon”); an inner capsuleor other container (“inner container”) that contains one or more CO₂generating components and that is present inside the lumen of theballoon; and an outer capsule, container, or coating (“outer container”)that contains the balloon. The balloon further comprises a self-sealingvalve system, preferably attached to the inner surface of the balloon byan adhesive or other means (e.g., welding), and an inoculation spacer toprevent puncture of the wall of the balloon and inner container by aneedle or other means for injecting an liquid activation agent into thelumen of the balloon via the self-sealing valve. The outer containerpreferably incorporates the balloon in a compacted state (e.g., foldedand rolled) with sufficient space to allow for activation liquid to beinjected into the balloon. The liquid activation agent initiatesseparation, erosion, degradation, and/or dissolution of the innercontainer and generation of CO₂ upon contact with the inflation agentcontained within the inner container, which subsequently causes outercontainer separation, erosion, degradation, and/or dissolution due toCO₂ gas pressure.

FIG. 44A depicts selected components of a swallowable, self-inflatingintragastric balloon system of a preferred embodiment, including asilicone head 441 with radioopacity ring 442, trimmed 30D siliconeseptum 443, Nylon 6 inoculation spacer 444, compacted balloon 445, innercontainer 446, and outer container 447 as constituents of the system inunassembled form. FIG. 44B depicts a fully assembled outer container 447including vent hole 448 aligned with septum 449 for puncture to injectliquid activation agent. As discussed further below, the components ofparticularly preferred systems possess the attributes described herein;however, in certain embodiments systems can be employed which utilizecomponents having other attributes and/or values.

Balloon

The balloon is fully sealed 360 degrees around with no external openingor orifice to the central lumen. The balloon has an “inverted”configuration. The term “inverted” as used herein is a broad term, andis to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a balloon having asmooth external surface with seams, welds, or the inside the balloon. Inorder to create a balloon with an inverted configuration, e.g., aballoon with no external seam allowance (no wall material between theedge of the balloon and the weld, seam, or other feature joining thesides together), two balloon halves are joined together in some fashion(e.g., adhered using adhesive or heat or the like based on the balloonmaterial used). One of the balloon halves encompasses an opening toallow for the balloon to be pulled through itself after adherence of thetwo halves and to have the seams of the balloon on the inside. Theopening created is preferably circular but can be any similar shape, andthe diameter of the opening preferably does not exceed 3.8 cm; however,in certain embodiments a larger diameter may be acceptable. A patch ofmaterial is adhered (adhesively, heat welded, or the like, based on thematerial used) to cover the original balloon-half opening. The inversionhole thus created that is subsequently patched is small enough that theforces exerted during inflation do not compromise the material used tomaintain CO₂ gas in the balloon. The preferred shape for the inflatedballoon in final assembly is ellipsoid, preferably spheroid or oblatespheroid, with nominal radii of from 1 inch (2.5 cm) to 3 inches (7.6cm), a nominal height of from 0.25 inches (0.6 cm) to 3 inches (7.6 cm),a volume of from 90 cm³ to 350 cm³ (at 37° C. and at internal nominalpressure and/or full inflation), an internal nominal pressure (at 37°C.) of 0 psi (0 Pa) to 15 psi (103421 Pa), and a weight of less than 15g. The balloon is configured for self-inflation with CO₂ and isconfigured to retain more than 75% of the original nominal volume for atleast 25 days, preferably for at least 90 days when residing in thestomach.

A self-sealing valve system is attached to the balloon (e.g., on itsinside surface) without the use of an opening, orifice, or other conduitin the wall of the balloon. The valve system utilizes a septum with adurometer of 20 Shore A to 60 Shore D. The valve is inserted orotherwise fabricated into a retaining structure that has a higherdurometer, e.g., 40 Shore D to 70 Shore D or more. The retainingstructure is fabricated from a silicone, rubber, soft plastic or anysuitable non-metallic polymeric material such as an acrylic, an epoxy, athermoplastic elastomer, or thermoplastic polyurethane. Preferably, astructure, such as a ring, that is metallic or non-metallic butradioopaque (e.g., barium) and visible under X-ray, is embedded in theretaining structure. Using a mechanical fit mechanism of two structuresof different durometers, one softer (septum) with a large diameter, isinserted into a snug, more rigid durometer structure creates compressiveforces in the once open orifice to enable CO₂ retention and reducesusceptibility for CO₂ gas leaks. The metallic ring for radio-opacityalso helps to create compressive forces on the septum. The self-sealingseptum allows air to be evacuated from the balloon forprocessing/compacting and inserting in the outer container, and alsoallows for the inflation agent to be injected into the outer containerfor inflation initiation. Additional septums can be provided, ifdesired; however, it is generally preferred to employ a single septum soas to maintain the volume of the deflated/folded balloon (and thus theouter capsule) as small as possible. The valve system is preferablyattached to the inner surface of the balloon such that a shear forcegreater than 9 lbs (40 N) is required to dislodge the valve system.FIGS. 45A-B depict various views of a silicone head 451 and opacity ring452 of a self-sealing valve system 450 of a preferred embodiment: FIGS.46A-C depict various views of a wedge-shaped septum 460 of a preferredembodiment.

Inner Container

The inner container is contained within the lumen of the balloon andcontains the CO₂ generator for balloon self-inflation. The CO₂ generatorcomprises an inflation agent mixture housed within the container.Preferably, from about 10% to about 80% of the total inflation agentused comprises powdered citric acid, with the remainder comprisingpowdered sodium bicarbonate. Sufficient inflation agent is provided suchthat upon completion of the CO₂ generating reaction, the balloonachieves inflation at the nominal inflation pressure described above.Preferably, a total of from about 0.28 to 4 grams inflation agentmixture is employed, depending upon the balloon size to be inflated;preferably up to 1.15 grams of sodium bicarbonate is used with theremainder being powdered citric acid to generate 300 cm³ of CO₂ atnominal pressure.

The inflation agent is compressed, formed or otherwise held in a shapewhich provides good surface area availability for the reactants for CO₂generation, while minimizing the space and/or volume sufficient to holdthe inner container. Preferably, the inner container has a length(longest dimension) of from about 0.748 inches (1.9 cm) to 1.06 inches(2.7 cm) and a diameter or width of from about 0.239 inches (0.6 cm) toabout 0.376 inches (1 cm). The volume of the inner container ispreferably from about 0.41 ml to about 1.37 ml. The inner container ispreferably in the form of a standard gelatin capsule but a gelatin tapemay be used in lieu of a push fit capsule. The container is preferablyrelied upon for containing the inflation agent; however, additionalsealing or other encapsulation can be employed to control timing ofinflation. Gelatin is particularly preferred for use as the innercontainer; however other materials can also be suitable for use, e.g.,cellulose. In order to minimize the internal volume of the system, it isgenerally preferred to include only a single inner container; however,in certain embodiments two or more internal containers canadvantageously be employed. Timing of self-inflation is selected basedon a normal esophageal transit time and a normal time of gastricemptying of large food particles, such that the balloon does not inflateto a size that would block the esophageal passageway or prematurely passthrough the pyloric sphincter. Timing is also derived by compacting theballoon such that the activation agent is substantially localized in theballoon next to the inner capsule, creating an efficient CO₂self-inflation method. I was able to get through the body this eveningand attached are a few edits (very minor). Balloon inflation isinitiated by the liquid activation agent causing degradation of theinner container, such that the inflation agent in the inner containercontacts the liquid activation agent, thereby initiating the gasgeneration reaction.

An inoculation spacer is preferably incorporated to guide a needle intothe self-sealing valve for injection of liquid activation agent into thelumen of the balloon and to prevent the needle from penetrating the wallof the deflated/folded balloon elsewhere such that pressure within thelumen of the balloon cannot be maintained. The inoculation spacer alsofacilitates preventing liquid activation agent from penetrating theinner container or the folded balloon material, thereby focusing theactivation agent in an appropriate manner to properly mix the reactantsfor CO₂ generation according to the criteria described above. Theinoculation spacer is generally in the form of a tube or cylinder. Theinoculation spacer is preferably attached to the inner container and/orthe self-sealing valve system with an adhesive or other fixing means;however, in certain embodiments the inoculation spacer can be“free-floating” and maintained in position by the folding or rolling ofthe walls of the balloon. The inoculation spacer can comprise anysuitable material that can be passed after separation, erosion,degradation, digestion, and/or dissolution of the outer container;however, preferable materials include non-metallic materials with aminimum Shore D durometer of 40 or more, any metallic material, or acombination thereof. FIGS. 47A-E depict various views of a cupped needlestop (inoculation spacer) 470 of a preferred embodiment.

Outer Container

The balloon is preferably provided in a deflated and folded state in acapsule or other retaining, containing or coating structure (“outercontainer”). The outer container is preferably in the form of a standardpush-fit gelatin capsule, with the push-fit relied upon for containingthe deflated/folded balloon; however, a gelatin wrap can advantageouslybe employed in certain embodiments. Gelatin is particularly preferredfor use as the outer container; however other materials can also besuitable for use, e.g., cellulose, collagen, and the like. Preferably,the outer container has a length (longest dimension) of from about 0.95inches (2.4 cm) to 2.5 inches (6.3 cm) and a diameter or width of fromabout 0.35 inches (0.9 cm) to about 0.9 inches (2.4 cm). The volume ofthe inner container is preferably from about 1.2 ml to about 8.25 ml.The outer container is preferably configured with one or more holes,slits, passageways or other egresses, preferably on each end, which actas vents such that any gas created due to inflation agent exposure tocondensation or other ambient moisture present during processing doesnot cause premature separation or degradation of the inner containerprior to 30 seconds after inoculation of the liquid activation agent,which may have an undesirable effect on reaction efficiency. The outercapsule degrades (e.g., separates, dissolves, or otherwise opens) due topressure build up caused by inflation of the balloon.

Inflation

The swallowable, self-inflating intragastric balloon is provided withmechanisms to reliably control timing of self-inflation such thatpremature inflation while in the esophagus during swallowing is avoidedand sufficient inflation once in the stomach so as to prevent passagethrough the pyloric sphincter is ensured. Normal esophageal transit timefor large food particles has been documented as 4-8 seconds, and gastricemptying of large food particles through the pylorus does not occur forat least 15-20 minutes. The outer container is preferably configured toseparate, dissolve, degrade, erode, and/or otherwise allow thedeflated/folded balloon to begin unfolding not less than 60 seconds butnot more than 15 minutes after inoculation with liquid activation agent.The inner container is preferably configured chemically, mechanically ora combination thereof to retard the initial CO₂ generating chemicalreaction such that sufficient CO₂ to begin inflating the balloon is notavailable earlier than 30 seconds after inoculation with the liquidactivation agent, but to permit generation of sufficient CO₂ such thatat least 10% of the occupyable volume of the balloon is filled within 30minutes, at least 60% of the occupyable volume of the balloon is filledwithin 12 hours, and at least 90% of the occupyable volume of theballoon is filled within 24 hours. This timing allows for injection ofthe activation agent into the outer container by the medicalprofessional, passing the device to the patient, and swallowing bynormal peristaltic means by the patient. This timing also prohibitspotential passing of an uninflated balloon into the duodenum by theballoon being inflated to a sufficient size such that gastric emptyingof the balloon would not be easy, as objects more than 7 mm in diameterdo not readily pass.

The activation agent is preferably injected using a syringe having aneedle with a gauge diameter of from 25 to 32. The needle length ispreferably from about 0.25 inches (0.6 cm) to 1 inches (2.54 cm) inlength so as to create a flow rate that allows for delivery of the fullvolume of inflation agent within 30 seconds, but in a manner/stream/flowthat does not physically damage the inner container, thereby causingpremature CO₂ generation and inflation. The activation agent ispreferably pure water, or a solution containing up to 50% concentrationof anhydrous citric acid at 20° C., or the equivalent thereof at varyingsolution temperatures based on solubility of anhydrous citric acid.Preferably, the system is configured to have an occupyable void space inthe central lumen of the balloon when in compacted form in the outercontainer of from about 0.3 ml to about 4.5 ml, such that acorresponding volume of activation agent can be injected into the voidspace.

Prior to placement in the outer container of the balloon containing theinner container, the balloon is deflated and folded. In a deflatedstate, the balloon is flat, with the inverted seam extending around theperimeter of the balloon. The self-sealing valve system is affixed tothe inner wall of the lumen close to the center of the deflated balloon,with the inner container positioned adjacent to the self-sealing valvesystem. The walls of the balloon are then folded. As part of the balloondesign, the self-sealing valve system is manufactured in a manner suchthat it is placed “off center” to minimize the number of folds uponthemselves (e.g., doubling or tripling up) required to fit the balloonin the outer container. For example, the self-sealing valve system canadvantageously be placed ½ r±¼ r from the center of the balloon, whereinr is the radius of the balloon along a line extending from the center ofthe balloon through the septum.

Prior to folding, the free-floating inner container with inflation agentfor CO₂ generation is preferably vertically aligned with theself-sealing valve system such that the septum/inoculation spacer isplaced directly above the tip of the capsule (FIG. 48A). The balloon 480contains an inner container 481. A self-sealing valve system 482 isadhesively adhered to the interior of the wall 483 of the balloon, andthe inverted configuration of the balloon is provided by inversionthrough a hole sealed with a patch 484. The top approximate ¼ of theballoon wall is folded over the inner capsule, and the pleats where thecapsule is are creased similar to the pleats formed in the second stepof making a paper airplane, then folded over to the left or to the right(FIG. 48B). The bottom approximate ¾ of the sphere is then accordionedusing no more than 2 creases and folded over the capsule (FIG. 48C-E).The left half is then folded over the right half of the capsule or viceversa so that the wings touch (FIG. 48F). Then the material is rolledover until it creates a tight roll (FIG. 48G). The device is then placedin the outer container.

The balloon is folded so as to form a pocket around the inner capsule isformed to insure that the liquid injected through the self-sealing valvesystem is contained in an area less than 10% of the entire balloonsurface area. The balloon is folded such that the number of total foldsis minimized so as to minimize possible damage to the outer material orcompromise of CO₂ barrier properties. The number of total folds ispreferably less than 10 folds. The balloon material is rolled when atall possible such that the number of creases required to fit the balloonin an outer container is minimized. This is done in effort to also toprevent lumen material damage. The self-sealing valve is also preferablyconstructed off-center of the balloon so as to minimize the number offolds that layer on top of each other.

The material forming the wall of the balloon is processed and folded tomaximize reaction efficiency by localizing the initiation agent injectedinto the balloon so that it is maintained proximal to the reactantswithin the inner container. The balloon is folded such that once thereaction initiates and the outer container separates, the balloonunfolds in a manner that creates the largest possible surface area,which prohibits the balloon from readily passing through the pyloricsphincter. The ratio of reactants in the inflation agent and activationagent are selected such that the pH of any remnant liquid inside thelumen of the balloon is acidic, with a pH of less than 6, such that anyballoon leakage or breach that allows stomach acid to enter does notcause additional CO₂ generation and resulting unintentionalre-inflation.

Deflation

The swallowable, self-inflating intragastric balloon is provided withmechanisms to reliably control timing of deflation. In preferredembodiments, the balloon auto-deflates and passes through the stomach,through the lower gastrointestinal tract, and out of the body. In thepreferred embodiments described below, the timing of deflation can beaccomplished via the external gastric environment (by conditions oftemperature, humidity, solubility, and/or pH, for example) or via theenvironment within the lumen of the inflated balloon.

In other embodiments, the patch applied to allow for inverted seams asdescribed above and/or one or more additional patches or otherstructures added to the balloon construction are made out of anerodible, degradable, or dissolvable material (natural or synthetic) andare incorporated into the wall of the balloon. The patch(s) are ofsufficient size to ensure opening of a sufficient surface area to causerapid deflation, and to prevent re-inflation by seepage of stomach fluidinto the balloon. The balloon patch(s) comprise materials that can beapplied to the balloon such that a substantially smooth surface ismaintained, and preferably comprise a single layer or multi-layeredmaterial. The patch(s) are constructed using an erodible, disintegrable,degradable or other such material that is preferably tissue-compatibleand degrades into non-toxic products or is a material that slowlyhydrolyzes and/or dissolves over time (e.g., poly(lactic-co-glycolicacid) (PLGA), polyvinyl alcohol (PVOH), polylactic acid (PLA),poly-L-lactic acid PLAA, Pullulan, Polyethylene Glycol (PEG),polyanhydrides, polyorthoesters, polyaryletherketones (PEEK),multi-block polyetheresters, poliglecaprone, polydioxanone,polytrimethylene carbonate, and other similar materials). Theseerodible, disintegrable, or degradable materials can be used alone, orin combination with other materials, or can be cast into/co-extruded,laminated, and/or dip coated in conjunction with non-erodible polymers(e.g., PET or the like) and employed in the construction of the balloon.Degradation/erosion occurs, is initiated by, and/or is controlled by thegastric environment (e.g., by conditions of temperature, humidity,solubility, and/or pH, for example), or is controlled within the lumenof the balloon (e.g., by conditions of humidity and/or derived pH, forexample) based on what the patch is exposed to. Thickness of the polymeras well as environment which affects degradation and time of exposurecan also facilitate degradation timing. Degradation/erosion are timedsuch that they occur once the pre-determined balloon useful life iscompleted (e.g., inflation is maintained for from 25 to 90 days in vivoin the stomach before degradation/erosion results in formation of anopening permitting deflation). As an alternative to (or in connectionwith) using an degradable material for the patch, the patch can comprisea similar CO₂ barrier film or the same film as the remaining wall of theballoon which is adhered to the balloon using a weak adhesive, or weldedor adhered such that after a specified amount of time the patchdelaminates from the applied area and allows for an opening for CO₂release for deflation. The mechanism of using an erodible material, or amaterial that mechanically fails after a pre-specified time is besimilar for all embodiments for deflation mechanisms described below aswell. The timing of degradation or erosion can be controlled using theexternal gastric environment (e.g., by conditions of temperature,humidity, solubility, and/or pH, for example) and/or can be controlledby conditions within the lumen of the balloon (e.g., by conditions ofhumidity and/or pH of residual liquid in the balloon).

In other embodiments, a plug or plugs (optionally in conjunction anotherdegradable retaining structure) can be incorporated into the balloonconstruction and can consist, all or in part, of an erodible,disintegrable, or otherwise degradable synthetic or natural polymersimilar to those described above (e.g., PLGA, PLAA, PEG, or the like).The plug can be formed into various shapes (e.g., cylinder shape) toachieve various surface-to-volume ratios so as to provide a preselectedand predictable bulk degradation pattern for the erodible polymer. Theplug can incorporate a releasing mechanism that can be chemicallyinitiated after degradation/erosion begins, such that the septum or plugmaterial pops out of the balloon or falls inside of the balloon, therebycreating a passageway for CO₂ gas release and subsequent deflation ofthe balloon. Mechanical additions that can be used in conjunction with aplug include a compressed spring housed within the retaining structureor plug structure, or a degradable/erodible/disintegrable material thatholds a plug (e.g., of a nondegradable or degradable material) in place.Once the material degrades, the spring is released and/or theplug/septum is pulled into the balloon or pushed out of the balloon,thus releasing CO₂ gas once an orifice has been created by release ofthe spring mechanism and pushing out or pulling in of the plug.

In certain embodiments, the balloon can incorporate one or more plugs inthe wall of the balloon that contain a compressed pellet or gasreleasing pellet. The pellet can be comprised of any combination ofconstituents that, when activated, emit CO₂ gas (e.g., sodiumbicarbonate and citric acid, or potassium bicarbonate and citric acid,or the like). The pellet can be in tablet or rod form protected by anerodible, disintegrable, or degradable material that is preferablytissue-compatible and degrades into non-toxic products or that slowlyhydrolyzes and/or dissolves similarly to the plugs and patches describedabove (e.g., poly(lactic-co-glycolic acid) (PLGA), polyvinyl alcohol(PVOH), polylactic acid (PLA), poly-L-lactic acid PLAA, Pullulan,Polyethylene Glycol, polyanhydrides, polyorthoesters,polyaryletherketones (PEEK), multi-block polyetheresters,poliglecaprone, polydioxanone, polytrimethylene carbonate, and otherlike materials). Degradation/erosion of the plug initiates the reactionof the two chemicals in the pellet and subsequently leads to formationof gas (e.g., CO₂). As sufficient gas is trapped or built up, sufficientpressure is eventually generated to push out the softened polymermaterial and create a larger channel for the CO₂ gas in the balloon toescape. External pressure applied by the stomach to the balloon (e.g.,squeezing) can contribute to the process of creating a larger channel.Dimensions and properties of the plug (diameter, thickness, composition,molecular weight, etc.) comprised of the polymer drives the timing ofdegradation.

In other embodiments, plugs or patches of different shapes or sizessimilar to those of the plugs described above can be employed within theballoon lumen in a multi-layer configuration including a semi-permeablemembrane to facilitate balloon deflation. The plug or patch is made ofsimilar degradable/erodible/dissolvable material as described above(e.g., poly(lactic-co-glycolic acid) (PLGA), polyvinyl alcohol (PVOH),polylactic acid (PLA), PLAA, pullulan, and other like materials) andcontains a compartment enclosed by a semi-permeable membrane(impermeable to an osmolyte) that contains a concentrated solution of asolute or osmolyte (such as glucose, sucrose, other sugars, salts, orcombination thereof). Once the plug or patch begins to degrade or erode,the water molecules move by osmosis down the water gradient from theregion of greater water concentration to the region of lower waterconcentration across the semi-permeable membrane into the hypertonicsolution in the compartment. The compartment containing the osmolyteswells and eventually bursts, pushing the membranes and the degradedplug or patch out, thereby allowing rapid gas loss through the newlycreated channels or areas.

Another mechanism for self-deflation is to create a forced de-laminationscheme, which can provide a larger surface area to ensure rapiddeflation. In, e.g., a balloon having a tri-layer wall, the outermostlayer is substantially strong enough to hold CO₂ (e.g., polyethyleneterephthalate (PET) or the like), the middle layer is comprised entirelyof an erodible material (e.g., PVOH or the like) while the inner layeris comprised of a weaker material (e.g., polyethylene (PE) or the like).The PET or outermost layer is “scored” or hatched with erodible materialto create small channels that erode over time. This creates channelssuch that the gastric fluid seeps into the balloon layers and startsdegrading the fully erodible material. When the erodible layer degradesor dissolves, the material that composes the innermost layer alsoerodes, degrades or dissolves since it is not strong enough to withstandthe gastric forces/environment on its own. The balloon then collapses onitself and eventually passes through the lower gastrointestinal tract.Having an erodible layer sandwiched between a strong and weak layerfacilitates timing of erosion by creating a longer path length than anerodible plug or patch affected by the gastric environment. The distancebetween scores or openings can also be selected so as to provide adesired deflation rate.

A mechanism to facilitate passing involves an erosion mechanism thatallows for the balloon to be broken down into a size that has a higherprobability of predictably passing through the lower gastrointestinalsystem. Preferably, the size of the balloon as deflated is less than 5cm long and 2 cm thick (similar to various foreign objects of similarsize that have been shown to pass predictably and easily through thepyloric sphincter). This can be accomplished by providing the balloonwith “erodible seams”. One seam that breaks the balloon open into (at aminimum) two halves, or more seams are provided so that a plurality ofsmaller balloon pieces is produced in the dissociation reaction. Thenumber of seams used can be selected based on the original surface areaof the balloon and what is required to dissociate the balloon intopieces that are of a size that can predictably pass through thegastrointestinal tract more easily. The rate of seam erosion can becontrolled by using a material affected by, e.g., the external gastricenvironment pH, liquid, humidity, temperature, or a combination thereof.Seams can be single layer consisting of only erodible material, ormulti-layer. The timing of self-deflation can be further controlled bythe design of the seam layers, e.g., making the reaction and/ordegradation of the seam material dependent on the internal environmentof the balloon instead of the external environment. By manipulating thereaction such that erosion or degradation is initiated by the internalenvironment (e.g., the balloon's internal pH, humidity, or otherfactors), any impact of person-to-person gastric variability (pH, etc.)that could affect erosion timing is minimized. The internal balloonenvironment can be manipulated by adding excess water at injection tocreate a more humid internal environment, or the amount of constituentsadded can be varied to manipulate the pH, etc.

The present invention has been described above with reference tospecific embodiments. However, other embodiments than the abovedescribed are equally possible within the scope of the invention.Different method steps than those described above, performing the methodby hardware or software, may be provided within the scope of theinvention. The different features and steps of the invention may becombined in other combinations than those described. The scope of theinvention is only limited by the appended patent claims.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

To the extent publications and patents or patent applicationsincorporated by reference herein contradict the disclosure contained inthe specification, the specification is intended to supersede and/ortake precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein.

Terms and phrases used in this application, and variations thereof,unless otherwise expressly stated, should be construed as open ended asopposed to limiting. As examples of the foregoing, the term ‘including’should be read to mean ‘including, without limitation’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; adjectives suchas ‘known’, ‘normal’, ‘standard’, and terms of similar meaning shouldnot be construed as limiting the item described to a given time periodor to an item available as of a given time, but instead should be readto encompass known, normal, or standard technologies that may beavailable or known now or at any time in the future; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the invention. Likewise, a group of itemslinked with the conjunction ‘and’ should not be read as requiring thateach and every one of those items be present in the grouping, but rathershould be read as ‘and/or’ unless expressly stated otherwise. Similarly,a group of items linked with the conjunction ‘or’ should not be read asrequiring mutual exclusivity among that group, but rather should be readas ‘and/or’ unless expressly stated otherwise. In addition, as used inthis application, the articles ‘a’ and ‘an’ should be construed asreferring to one or more than one (i.e., to at least one) of thegrammatical objects of the article. By way of example, ‘an element’means one element or more than one element.

The presence in some instances of broadening words and phrases such as‘one or more’, ‘at least’, ‘but not limited to’, or other like phrasesshall not be read to mean that the narrower case is intended or requiredin instances where such broadening phrases may be absent.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it is apparent to those skilled in the art that certainchanges and modifications may be practiced. Therefore, the descriptionand examples should not be construed as limiting the scope of theinvention to the specific embodiments and examples described herein, butrather to also cover all modification and alternatives coming with thetrue scope and spirit of the invention.

1-20. (canceled)
 21. A drug delivery system comprising: avolume-occupying subcomponent comprising a self-sealing valve systemattached to a wall of a balloon in a central lumen of the balloon by anadhesive with a shear force greater than about 40 N, the self-sealingvalve system comprising a septum, a retaining structure, and acontinuous ring, wherein the septum has a durometer that is less than adurometer of the retaining structure, wherein the continuous ring isconfigured to exert a compressive force on the septum, wherein thevolume-occupying subcomponent has a weight of less than about 15 g,wherein the volume-occupying subcomponent is configured to have a shapeupon full inflation selected from the group consisting of ellipsoid,spheroid, and oblate spheroid, and wherein the volume-occupyingsubcomponent is configured to have a volume of from about 90 cm³ toabout 350 cm³ upon full inflation; and a drug delivery subcomponent. 22.The system of claim 21, wherein the drug delivery subcomponent furthercomprises a pharmaceutical substance.
 23. The system of claim 22,wherein the pharmaceutical substance is incorporated into a materialforming the volume-occupying subcomponent.
 24. The system of claim 22,wherein the pharmaceutical substance is incorporated into one or morebarrier coatings of the volume-occupying subcomponent or a lubriciouscoating applied to the volume-occupying subcomponent
 25. The system ofclaim 24, wherein the one or more barrier coatings comprise a polymer,and wherein release or diffusion properties of the pharmaceuticalsubstance are preselected by modifying characteristics of the polymer orby changing a ratio of hydrophobic to hydrophilic molecules in thecomposition of the polymer.
 26. The system of claim 21, wherein the drugdelivery subcomponent comprises a pharmaceutical substance in at leastone degradable pocket formed on an interior surface or an exteriorsurface of the volume-occupying subcomponent.
 27. The system of claim21, wherein the drug delivery subcomponent comprises a pharmaceuticalsubstance coated on the outside of the volume-occupying subcomponent.28. The system of claim 27, wherein the pharmaceutical substance isincorporated or implanted into a polymer which is sprayed, sputtercoated, vapor deposited or applied in liquid form onto an outside of thevolume-occupying subcomponent.
 29. The system of claim 27 wherein thedrug delivery subcomponent comprises a microporous, microsphere, ormeshed exterior on the outside of the volume-occupying subcomponent. 30.The system of claim 21, wherein the drug delivery subcomponent comprisesa pharmaceutical substance incorporated into an interior volume of thevolume-occupying subcomponent.
 31. The system of claim 21, wherein thedrug delivery subcomponent comprises a pharmaceutical substanceincorporated into a subcompartment of the volume-occupying subcomponent.32. The system of claim 22, wherein the drug delivery subcomponent isconfigured to gradually release the pharmaceutical substance by a pump,a valve, a head breakage, or a disintegration of a head component. 33.The system of claim 21, wherein the pharmaceutical substance is fixed ina biodegradable plug material configured to release the pharmaceuticalsubstance as the biodegradable plug material degrades in the stomach.34. The system of claim 21, wherein an outer layer of thevolume-occupying subcomponent possesses antimicrobial properties. 35.The system of claim 22, wherein the pharmaceutical substance comprisessilver ions, and wherein a wall of the volume occupying device comprisesa material adapted for ion transfer across it, such that, in vivo, thesilver ions diffuse out of the volume-occupying subcomponent or onto itsexterior surface, thereby imparting antimicrobial properties to thevolume-occupying subcomponent.
 36. The system of claim 21, wherein thedrug delivery subcomponent is one or more reservoirs in thevolume-occupying subcomponent adapted to contain a pharmaceuticalsubstance.
 37. The system of claim 36, further comprising a drug polymeror combination of drug polymers positioned in the one or morereservoirs.
 38. The system of claim 21, wherein the drug deliverysubcomponent is a plurality of microcapsules on an exterior of thevolume-occupying subcomponent, each microcapsule carrying a drug orcombination of drugs.
 39. The system of claim 21, wherein the drugdelivery subcomponent comprises creases in the volume-occupyingsubcomponent in its is in is delivery form adapted to contain apharmaceutical substance, and to release the pharmaceutical substanceupon expansion of the volume-occupying subcomponent.
 40. The system ofclaim 21, wherein the drug delivery subcomponent comprises multipledrugs and is adapted and to release selected drugs upon command.
 41. Thesystem of claim 21, wherein the drug delivery subcomponent comprisesdrugs layered on top of one another or adjacent to each other on certainportions of the volume-occupying subcomponent.